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href='#corrigendum'> Corrigendum </a> </li> </ul> </div> </div> <div class='row'> <div class='small-12 columns'> <h5>Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling</h5> </div> <div class='small-12 columns'> <p><p><a href="https://insight.jci.org/articles/view/183684">Fan et al.</a> report that parathyroid hormone 1 receptor (PTH1R) couples bone formation and bone resorption by negatively regulating Hedgehog signaling and IGF1 production. The cover image shows a mouse molar with colocalized Gli1+ mesenchymal stem cells (red) and Runx2+ osteoblasts (green) during development.</p> </p> </div> </div> <a class='in-page' name='research_article'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel0' name='research_article'> <strong></strong> <span class='toggle-icon'></span> Research Articles </a> <div class='content active' id='panel0'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/165837">Regulation of lung progenitor plasticity and repair by fatty acid oxidation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/165837">Quetzalli D. Angeles-Lopez, … , Mauricio Rojas, Ana L. Mora</a> <a class='hide-for-small show-more' data-reveal-id='article7202-more' href='#'> <div class='article-authors'> Quetzalli D. Angeles-Lopez, … , Mauricio Rojas, Ana L. Mora </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e165837. <a href="https://doi.org/10.1172/jci.insight.165837">https://doi.org/10.1172/jci.insight.165837</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/165837">Text</a> | <a href="/articles/view/165837/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.165837' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/165837/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/165000/165837/small/jci.insight.165837.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7202-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/165837">Regulation of lung progenitor plasticity and repair by fatty acid oxidation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/165837">Text</a></li> <li><a class="button tiny" href="/articles/view/165837/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Quetzalli D. Angeles-Lopez, Jhonny Rodriguez-Lopez, Paula Agudelo Garcia, Jazmin Calyeca, Diana Álvarez, Marta Bueno, Lan N. Tu, Myriam Salazar-Terreros, Natalia Vanegas-Avendaño, Jordan E. Krull, Aigul Moldobaeva, Srimathi Bogamuwa, Stephanie S. Scott, Victor Peters, Brenda F. Reader, Sruti Shiva, Michael Jurczak, Mahboobe Ghaedi, Qin Ma, Toren Finkel, Mauricio Rojas, Ana L. Mora</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/173071">Mindin regulates fibroblast subpopulations through distinct Src family kinases during fibrogenesis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173071">Sunny Kataria, … , Akash Gulyani, Colin Jamora</a> <a class='hide-for-small show-more' data-reveal-id='article7213-more' href='#'> <div class='article-authors'> Sunny Kataria, … , Akash Gulyani, Colin Jamora </div> </a> <span class='article-published-at'> Published December 31, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e173071. <a href="https://doi.org/10.1172/jci.insight.173071">https://doi.org/10.1172/jci.insight.173071</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173071">Text</a> | <a href="/articles/view/173071/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.173071' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/173071/figure/1' ref='group' title='SCA1+ fibroblast localization is perturbed in the dermis of Snail-transgenic mice. Representative contour plot showing quadrants for (A) α-SMA+SCA1+/CD26–VIMhi, α-SMA+SCA1-/CD26–VIMhi, α-SMA-SCA1+/CD26–VIMhi and α-SMA–SCA1–/CD26–VIMhi and (B) α-SMA+CD26+/SCA1–VIMhi, α-SMA+CD26–/SCA1–VIMhi, α-SMA–CD26+/SCA1–VIMhi and α-SMA–CD26–/SCA1–VIMhi cells from P9 WT (left) and Snail-transgenic (SnTg) (right) mice. Individual value plots (mean ± SEM) of (C) the percentage of α-SMA+SCA1+/CD26–VIMhi and (D) the percentage α-SMA+CD26+/SCA1–VIMhi cells (n = 6; P values were calculated by Welch’s t test; *P < 0.05, ***P < 0.001). (E) SCA1+ fibroblasts (green) and nuclear staining with DAPI (blue) in WT and SnTg skin sections in P3, P5, P7, and P9 pups. The white boxes mark the insets shown in Supplemental Figure 1J. Note that the green stain at the bottom of the skin section is the autofluorescence of the paper used to keep the tissue uncurled during the embedding process. (F) Heatmap showing the probability of SCA1+ cells at a given distance below the epidermis in WT (top) and SnTg (bottom) mice. P3 (n =3 WT and Snail Tg), P5 (n = 2 WT and n = 4 Snail Tg), P7 (n = 3 WT and n = 4 Snail Tg), and P9 (n = 6 WT and n = 8 Snail Tg). (G) CD26+ fibroblasts (red) and nuclear staining with DAPI (blue) in WT and SnTg skin sections from P3, P5, P7, and P9 pups. The white boxes mark the insets shown in Supplemental Figure 1L as magnified areas. The boxed areas are shown at higher magnification in Supplemental Figure 1L. Note that the red stain at the bottom of the skin section is the autofluorescence of the paper used to keep the tissue uncurled during the embedding process. (H) Heatmap showing the probability of CD26+ cells at a given distance below the epidermis in WT (top) and SnTg (bottom) at P3 (n = 2 WT and n = 3 Snail Tg), P5 (n = 2 WT and n = 3 Snail Tg), P7 (n = 3 WT and n = 3 Snail Tg), and P9 (n = 4 WT and n = 6 Snail Tg).'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/173000/173071/small/jci.insight.173071.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7213-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173071">Mindin regulates fibroblast subpopulations through distinct Src family kinases during fibrogenesis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173071">Text</a></li> <li><a class="button tiny" href="/articles/view/173071/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Fibrosis results from excessive extracellular matrix (ECM) deposition, which causes tissue stiffening and organ dysfunction. Activated fibroblasts, central to fibrosis, exhibit increased migration, proliferation, contraction, and ECM production. However, it remains unclear if the same fibroblast performs all of the processes that fall under the umbrella term of “activation.” Owing to fibroblast heterogeneity in connective tissues, subpopulations with specific functions may operate under distinct regulatory controls. Using a transgenic mouse model of skin fibrosis, we found that Mindin (also known as spondin-2), secreted by Snail-transgenic keratinocytes, differentially regulates fibroblast subpopulations. Mindin promotes migration and inflammatory gene expression in SCA1+ dermal fibroblasts via Fyn kinase. In contrast, it enhances contractility and collagen production in papillary CD26+ fibroblasts through c-Src signaling. Moreover, in the context of the fibrotic microenvironment of the tumor stroma, we found that differential responses of resident fibroblast subpopulations to Mindin extend to the generation of functionally heterogeneous cancer-associated fibroblasts. This study identifies Mindin as a key orchestrator of dermal fibroblast heterogeneity, reshaping cellular dynamics and signaling diversity in the complex landscapes of skin fibrosis and cancer.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sunny Kataria, Isha Rana, Krithika Badarinath, Rania F. Zaarour, Gaurav Kansagara, Sultan Ahmed, Abrar Rizvi, Dyuti Saha, Binita Dam, Abhik Dutta, Ravindra K. Zirmire, Edries Yousaf Hajam, Pankaj Kumar, Akash Gulyani, Colin Jamora</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/173746">EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173746">Emilie Jaune-Pons, … , Gwen Lomberk, Christopher L. Pin</a> <a class='hide-for-small show-more' data-reveal-id='article7209-more' href='#'> <div class='article-authors'> Emilie Jaune-Pons, … , Gwen Lomberk, Christopher L. Pin </div> </a> <span class='article-published-at'> Published December 31, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e173746. <a href="https://doi.org/10.1172/jci.insight.173746">https://doi.org/10.1172/jci.insight.173746</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173746">Text</a> | <a href="/articles/view/173746/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.173746' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/173746/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/173000/173746/small/jci.insight.173746.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7209-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173746">EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173746">Text</a></li> <li><a class="button tiny" href="/articles/view/173746/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Enhancer of zeste homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and gene repression. EZH2 is overexpressed in many cancers, and studies in mice attributed both prooncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in patients with PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2ΔSET), we showed that loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D) nor did it increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests that expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumor microenvironment and acinar cell differentiation.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Zachary Klassen, Abdessamad El Kaoutari, Kurt Berger, Charis Johnson, Mickenzie B. Martin, Saloni Aggarwal, Sukhman Brar, Muhammad Khalid, Joanna F. Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/174825">Glucose-dependent insulinotropic polypeptide receptor signaling alleviates gut inflammation in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/174825">Rola Hammoud, … , Chen Varol, Daniel J. Drucker</a> <a class='hide-for-small show-more' data-reveal-id='article7214-more' href='#'> <div class='article-authors'> Rola Hammoud, … , Chen Varol, Daniel J. Drucker </div> </a> <span class='article-published-at'> Published December 26, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e174825. <a href="https://doi.org/10.1172/jci.insight.174825">https://doi.org/10.1172/jci.insight.174825</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/174825">Text</a> | <a href="/articles/view/174825/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.174825' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/174825/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/174000/174825/small/jci.insight.174825.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7214-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/174825">Glucose-dependent insulinotropic polypeptide receptor signaling alleviates gut inflammation in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/174825">Text</a></li> <li><a class="button tiny" href="/articles/view/174825/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor–GLP-1 receptor (GIPR–GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist–GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil–induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Rola Hammoud, Kiran Deep Kaur, Jacqueline A. Koehler, Laurie L. Baggio, Chi Kin Wong, Katie E. Advani, Bernardo Yusta, Irina Efimova, Fiona M. Gribble, Frank Reimann, Sigal Fishman, Chen Varol, Daniel J. Drucker</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/176749">Highly multiplexed imaging reveals prognostic immune and stromal spatial biomarkers in breast cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176749">Jennifer R. Eng, … , Rosalie C. Sears, Koei Chin</a> <a class='hide-for-small show-more' data-reveal-id='article7221-more' href='#'> <div class='article-authors'> Jennifer R. Eng, … , Rosalie C. Sears, Koei Chin </div> </a> <span class='article-published-at'> Published January 14, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e176749. <a href="https://doi.org/10.1172/jci.insight.176749">https://doi.org/10.1172/jci.insight.176749</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176749">Text</a> | <a href="/articles/view/176749/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.176749' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/176749/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/176000/176749/small/jci.insight.176749.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7221-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176749">Highly multiplexed imaging reveals prognostic immune and stromal spatial biomarkers in breast cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176749">Text</a></li> <li><a class="button tiny" href="/articles/view/176749/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Spatial profiling of tissues promises to elucidate tumor-microenvironment interactions and generate prognostic and predictive biomarkers. We analyzed single-cell spatial data from 3 multiplex imaging technologies: cyclic immunofluorescence (CycIF) data we generated from 102 patients with breast cancer with clinical follow-up as well as publicly available mass cytometry and multiplex ion-beam imaging datasets. Similar single-cell phenotyping results across imaging platforms enabled combined analysis of epithelial phenotypes to delineate prognostic subtypes among patients who are estrogen-receptor+ (ER+). We utilized discovery and validation cohorts to identify biomarkers with prognostic value. Increased lymphocyte infiltration was independently associated with longer survival in triple-negative (TN) and high-proliferation ER+ breast tumors. An assessment of 10 spatial analysis methods revealed robust spatial biomarkers. In ER+ disease, quiescent stromal cells close to tumor were abundant in tumors with good prognoses, while tumor cell neighborhoods containing mixed fibroblast phenotypes were enriched in poor-prognosis tumors. In TN disease, macrophage/tumor and B/T lymphocyte neighbors were enriched, and lymphocytes were dispersed in good-prognosis tumors, while tumor cell neighborhoods containing vimentin+ fibroblasts were enriched in poor-prognosis tumors. In conclusion, we generated comparable single-cell spatial proteomic data from several clinical cohorts to enable prognostic spatial biomarker identification and validation.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jennifer R. Eng, Elmar Bucher, Zhi Hu, Cameron R. Walker, Tyler Risom, Michael Angelo, Paula Gonzalez-Ericsson, Melinda E. Sanders, A. Bapsi Chakravarthy, Jennifer A. Pietenpol, Summer L. Gibbs, Rosalie C. Sears, Koei Chin</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/176811">Angiotensin receptor blockers modulate the lupus CD4<sup>+</sup> T cell epigenome characterized by TNF family–linked signaling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176811">Andrew P. Hart, … , Daniel P. Beiting, Terri M. Laufer</a> <a class='hide-for-small show-more' data-reveal-id='article7206-more' href='#'> <div class='article-authors'> Andrew P. Hart, … , Daniel P. Beiting, Terri M. Laufer </div> </a> <span class='article-published-at'> Published December 17, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e176811. <a href="https://doi.org/10.1172/jci.insight.176811">https://doi.org/10.1172/jci.insight.176811</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176811">Text</a> | <a href="/articles/view/176811/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.176811' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/176811/figure/1' ref='group' title='Lupus Th cells retain open chromatin features that define T cell subsets. (A) Representative gating strategy to purify CD45RA+CD27+ naive Th, CXCR5+PD1+ICOS+CD38+ AcTfh, CXCR5+PD1+ICOS–CD38– cTfh, and CXCR5–PD1–CXCR3+ Th1 cells. PD1, programmed cell death 1; AcTfh, effector Tfh; cTfh, circulating Tfh. (B) Frequency of non-naive Th cells among CD4+ T cells in lupus (n = 14) and healthy individuals (n = 15) by flow cytometry. (C) Frequency of CXCR5+PD1+ T cells among CD4+ T cells in lupus (n = 14) and healthy individuals (n = 15). (D) Frequency of AcTfh cells among CD4+ T cells in lupus (n = 14) and healthy individuals (n = 15). (E) Principal component analysis (PCA) (PC1 × PC2) of ATAC-Seq data for sorted Th cell populations. (F) PCA (PC1 × PC5) of ATAC-Seq data for sorted Th cell populations. Colors distinguish lupus or healthy samples and shapes distinguish Th cell subsets. (G) The 10 most significant ChipEnrich pathway enrichment results for peaks defining non-naive CD4+ T cells in PC1. (H) Sample-wise peak-set variation analysis of ATAC-Seq data across lupus and healthy Th cell populations against published chromatin peaks enriched in naive Th cells. (I) Sample-wise peak-set variation analysis of published chromatin peaks enriched in GC Tfh cells across lupus and healthy Th cell populations. Error is reported as SD. ATAC-Seq data represent 25 naive Th cell samples (13 lupus, 12 healthy), 8 Th1 samples (4 lupus, 4 healthy), 24 cTfh samples (12 lupus, 12 healthy), and 24 AcTfh samples (12 lupus, 12 healthy). *P < 0.05, unpaired 2-tailed t tests (B–D, H, and I).'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/176000/176811/small/jci.insight.176811.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7206-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176811">Angiotensin receptor blockers modulate the lupus CD4<sup>+</sup> T cell epigenome characterized by TNF family–linked signaling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176811">Text</a></li> <li><a class="button tiny" href="/articles/view/176811/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from patients with lupus and healthy individuals. Most patients with lupus, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single-cell approaches revealed that chromatin changes extended to naive CD4+ T cells, uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNF-α, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs), which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Andrew P. Hart, Jonathan J. Kotzin, Steffan W. Schulz, Jonathan S. Dunham, Alison L. Keenan, Joshua F. Baker, Andrew D. Wells, Daniel P. Beiting, Terri M. Laufer</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/178827">Ablation of <i>Htra1</i> leads to sub-RPE deposits and photoreceptor abnormalities</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/178827">Pooja Biswas, … , Monica M. Jablonski, Radha Ayyagari</a> <a class='hide-for-small show-more' data-reveal-id='article7222-more' href='#'> <div class='article-authors'> Pooja Biswas, … , Monica M. Jablonski, Radha Ayyagari </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e178827. <a href="https://doi.org/10.1172/jci.insight.178827">https://doi.org/10.1172/jci.insight.178827</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/178827">Text</a> | <a href="/articles/view/178827/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.178827' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/178827/figure/1' ref='group' title='Photoreceptor function in Htra1–/– mice. (A–E) Mean photopic and scotopic responses of 1.5, 3, 5, 15, and 21m Htra1–/– mice compared and normalized to age-matched WT mice at 1.09 log cd·s/m2, 2.00 log cd·s/m2, and –3.5 log cd·s/m2 stimulation intensities. n = 5 mice per age point and genotype. Two-way ANOVA followed by the Tukey-Kramer for pairwise comparisons, with P values adjusted using the Bonferroni Correction. Age-matched comparisons are displayed. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/178000/178827/small/jci.insight.178827.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7222-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/178827">Ablation of <i>Htra1</i> leads to sub-RPE deposits and photoreceptor abnormalities</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/178827">Text</a></li> <li><a class="button tiny" href="/articles/view/178827/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The high-temperature requirement A1 (HTRA1), a serine protease, has been demonstrated to play a pivotal role in the extracellular matrix (ECM) and has been reported to be associated with the pathogenesis of age-related macular degeneration (AMD). To delineate its role in the retina, the phenotype of homozygous Htra1-KO (Htra1–/–) mice was characterized to examine the effect of Htra1 loss on the retina and retinal pigment epithelium (RPE) with age. The ablation of Htra1 led to a significant reduction in rod and cone photoreceptor function, primary cone abnormalities followed by rods, and atrophy in the RPE compared with WT mice. Ultrastructural analysis of Htra1–/– mice revealed RPE and Bruch’s membrane (BM) abnormalities, including the presence of sub-RPE deposits at 5 months (m) that progressed with age accompanied by increased severity of pathology. Htra1–/– mice also displayed alterations in key markers for inflammation, autophagy, and lipid metabolism in the retina. These results highlight the crucial role of HTRA1 in the retina and RPE. Furthermore, this study allows for the Htra1–/– mouse model to be utilized for deciphering mechanisms that lead to sub-RPE deposit phenotypes including AMD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Pooja Biswas, DaNae R. Woodard, T.J. Hollingsworth, Naheed W. Khan, Danielle R. Lazaro, Anne Marie Berry, Manisha Dagar, Yang Pan, Donita Garland, Peter X. Shaw, Chio Oka, Takeshi Iwata, Monica M. Jablonski, Radha Ayyagari</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181481">MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn’s disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181481">Elena Layunta, … , Bruce A. Vallance, Thaher Pelaseyed</a> <a class='hide-for-small show-more' data-reveal-id='article7187-more' href='#'> <div class='article-authors'> Elena Layunta, … , Bruce A. Vallance, Thaher Pelaseyed </div> </a> <span class='article-published-at'> Published December 19, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e181481. <a href="https://doi.org/10.1172/jci.insight.181481">https://doi.org/10.1172/jci.insight.181481</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181481">Text</a> | <a href="/articles/view/181481/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.181481' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/181481/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/181000/181481/small/jci.insight.181481.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7187-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181481">MUC17 is an essential small intestinal glycocalyx component that is disrupted in Crohn’s disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181481">Text</a></li> <li><a class="button tiny" href="/articles/view/181481/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Crohn’s disease (CD) is the chronic inflammation of the terminal ileum and colon triggered by a dysregulated immune response to bacteria, but insights into specific molecular perturbations at the critical bacteria-epithelium interface are limited. Here, we report that the membrane mucin MUC17 protected small intestinal enterocytes against commensal and pathogenic bacteria. In noninflamed CD ileum, reduced MUC17 levels and a compromised glycocalyx barrier allowed recurrent bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine particularly prone to atypical bacterial infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and in the extraintestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in patients with CD. Our findings highlight MUC17 as an essential region-specific line of defense in the small intestine with relevance for early epithelial defects in CD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Elena Layunta, Sofia Jäverfelt, Fleur C. van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara I.M. Thulin, Bruce A. Vallance, Thaher Pelaseyed</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182103">TRPC1 links calcium signaling to cellular senescence in the protection against posttraumatic osteoarthritis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182103">Meike Sambale, … , Thomas Pap, Joanna Sherwood</a> <a class='hide-for-small show-more' data-reveal-id='article7225-more' href='#'> <div class='article-authors'> Meike Sambale, … , Thomas Pap, Joanna Sherwood </div> </a> <span class='article-published-at'> Published December 24, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e182103. <a href="https://doi.org/10.1172/jci.insight.182103">https://doi.org/10.1172/jci.insight.182103</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182103">Text</a> | <a href="/articles/view/182103/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.182103' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/182103/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/182000/182103/small/jci.insight.182103.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7225-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182103">TRPC1 links calcium signaling to cellular senescence in the protection against posttraumatic osteoarthritis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182103">Text</a></li> <li><a class="button tiny" href="/articles/view/182103/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we have demonstrated that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence–associated cartilage breakdown during mechanical and inflammatory challenge. We revealed that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a nonredundant role in calcium signaling in chondrocytes. Trpc1–/– mice subjected to destabilization of the medial meniscus–induced OA developed a more severe OA phenotype than WT controls. During early OA development, Trpc1–/– mice displayed an increased chondrocyte survival rate; however, remaining cells displayed features of senescence including p16INK4a expression and decreased Sox9. RNA-Seq identified differentially expressed genes related to cell number, apoptosis, and extracellular matrix organization. Trpc1–/– chondrocytes exhibited accelerated dedifferentiation, while demonstrating an increased susceptibility to cellular senescence. Targeting the mechanism of TRPC1 activation may be a promising therapeutic strategy in OA prevention.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Meike Sambale, Starlee Lively, Osvaldo Espin-Garcia, Pratibha Potla, Chiara Pastrello, Sarah Bödecker, Linda Wessendorf, Simon Kleimann, Peter Paruzel, Rojiar Asgarian, Alexandra Tosun, Johanna Intemann, Jessica Bertrand, Francesco Dell’Accio, Mohit Kapoor, Thomas Pap, Joanna Sherwood</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182398">Endothelial GSDMD underlies LPS-induced systemic vascular injury and lethality</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182398">Enyong Su, … , Hong Jiang, Ming Liu</a> <a class='hide-for-small show-more' data-reveal-id='article7184-more' href='#'> <div class='article-authors'> Enyong Su, … , Hong Jiang, Ming Liu </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e182398. <a href="https://doi.org/10.1172/jci.insight.182398">https://doi.org/10.1172/jci.insight.182398</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182398">Text</a> | <a href="/articles/view/182398/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.182398' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/182398/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/182000/182398/small/jci.insight.182398.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7184-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182398">Endothelial GSDMD underlies LPS-induced systemic vascular injury and lethality</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182398">Text</a></li> <li><a class="button tiny" href="/articles/view/182398/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Enyong Su, Xiaoyue Song, Lili Wei, Junqiang Xue, Xuelin Cheng, Shiyao Xie, Hong Jiang, Ming Liu</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182429">AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182429">Huimou Chen, … , Suying Lu, Yizhuo Zhang</a> <a class='hide-for-small show-more' data-reveal-id='article7231-more' href='#'> <div class='article-authors'> Huimou Chen, … , Suying Lu, Yizhuo Zhang </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e182429. <a href="https://doi.org/10.1172/jci.insight.182429">https://doi.org/10.1172/jci.insight.182429</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182429">Text</a> | <a href="/articles/view/182429/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.182429' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/182429/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/182000/182429/small/jci.insight.182429.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7231-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182429">AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182429">Text</a></li> <li><a class="button tiny" href="/articles/view/182429/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Rhabdomyosarcoma (RMS) is one of the most common solid tumors in children and adolescents. Patients with relapsed/refractory RMS have limited treatment options, highlighting the urgency for the identification of novel therapeutic targets for RMS. In the present study, aurora kinase B (AURKB) was found to be highly expressed in RMS and associated with unfavorable prognosis of patients. Functional experiments indicated that inhibition of AURKB significantly reduced RMS cell proliferation, induced apoptosis and ferroptosis, and suppressed RMS growth in vivo. The highly expressed AURKB in RMS contributes to the apoptosis and ferroptosis resistance of tumor cells through the nucleophosmin 1 (NPM1)/Sp1 transcription factor (SP1)/acyl-CoA synthetase long-chain family member 5 (ACSL5) axis. Furthermore, inhibition of AURKB exerted an anti-RMS effect together with vincristine both in vitro and in vivo, with tolerable toxicity. The above findings provide insights we believe are new into the tumorigenesis of RMS, especially with regard to apoptosis or ferroptosis resistance, indicating that AURKB may be a potential target for clinical intervention in patients with RMS.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Huimou Chen, Mengzhen Li, Yu Zhang, Mengjia Song, Yi Que, Juan Wang, Feifei Sun, Jia Zhu, Junting Huang, Juan Liu, Jiaqian Xu, Suying Lu, Yizhuo Zhang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182615">Airway-resident memory CD4 T cell activation accelerates antigen presentation and T cell priming in draining lymph nodes</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182615">Caroline M. Finn, … , Tara M. Strutt, K. Kai McKinstry</a> <a class='hide-for-small show-more' data-reveal-id='article7207-more' href='#'> <div class='article-authors'> Caroline M. Finn, … , Tara M. Strutt, K. Kai McKinstry </div> </a> <span class='article-published-at'> Published December 17, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e182615. <a href="https://doi.org/10.1172/jci.insight.182615">https://doi.org/10.1172/jci.insight.182615</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182615">Text</a> | <a href="/articles/view/182615/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.182615' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/182615/figure/1' ref='group' title='IAV-primed lung CD4 Trm respond rapidly to i.n. administered antigen. (A) B6 mice received 1 × 106 naive CD90.1/CD90.2 OT-II cells i.v. followed by priming with PR8-OVAII. After 45 days, the primed mice were challenged with i.n. administered antigen to recall OT-II Trm in the lung. (B) Primed mice were treated at 45 dpi with fluorescent anti-CD4 Ab i.v. prior to lung harvest, with representative staining shown to identify donor OT-II cells (left), donor Trm shielding from labeling by i.v. administered CD4 Ab (center), and expression of CD69 by the i.v.shielded versus i.v.labeled OT-II cells (right). (C) Number of donor Trm (i.v.shielded) cells in interstitial and airway niches based on BAL harvest; n = 7/group; pooled from 2 experiments. (D) IAV-primed mice were given 50 μg of OVA or BSA, or PBS alone via i.n. administration. Representative CD69 (left) and CD25 (right) staining of total lung OT-II Trm 6 hours later. (E) The percentage of CD69hi (left) and CD25hi (right) donor Trm in airway (circles) and interstitial (triangle) niches from separate mice given OVA or PBS: n = 4–5 per group; results from 1 of 3 experiments. Student’s t test was used for pairwise comparison for C, and 1-way ANOVA with Tukey’s multiple-comparison test was used in E. *P < 0.05, **P < 0.01, ****P < 0.0001.'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/182000/182615/small/jci.insight.182615.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7207-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182615">Airway-resident memory CD4 T cell activation accelerates antigen presentation and T cell priming in draining lymph nodes</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182615">Text</a></li> <li><a class="button tiny" href="/articles/view/182615/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Specialized memory CD4 T cells that reside long-term within tissues are critical components of immunity at portals of pathogen entry. In the lung, such tissue-resident memory (Trm) cells are activated rapidly after infection and promote local inflammation to control pathogen levels before circulating T cells can respond. However, optimal clearance of Influenza A virus can require Trm and responses by other virus-specific T cells that reach the lung only several days after their activation in secondary lymphoid organs. Whether local CD4 Trm sentinel activity can affect the efficiency of T cell activation in secondary lymphoid organs is not clear. Here, we found that recognition of antigen by influenza-primed Trm in the airways promoted more rapid migration of highly activated antigen-bearing DC to the draining lymph nodes. This in turn accelerated the priming of naive T cells recognizing the same antigen, resulting in newly activated effector T cells reaching the lungs earlier than in mice not harboring Trm. Our findings, thus, reveal a circuit linking local and regional immunity whereby antigen recognition by Trm improves effector T cell recruitment to the site of infection though enhancing the efficiency of antigen presentation in the draining lymph node.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Caroline M. Finn, Kunal Dhume, Eugene Baffoe, Lauren A. Kimball, Tara M. Strutt, K. Kai McKinstry</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183483">Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183483">Joanna Y. Wang, … , David B. Frank, Lisa R. Young</a> <a class='hide-for-small show-more' data-reveal-id='article7190-more' href='#'> <div class='article-authors'> Joanna Y. Wang, … , David B. Frank, Lisa R. Young </div> </a> <span class='article-published-at'> Published December 19, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e183483. <a href="https://doi.org/10.1172/jci.insight.183483">https://doi.org/10.1172/jci.insight.183483</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183483">Text</a> | <a href="/articles/view/183483/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.183483' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/183483/figure/1' ref='group' title='Loss of AT2 cells in HPS mice starting at 8 weeks of age. (A) IF staining of whole-mount lung issue for pro-SPC and AGER in WT and HPS1/2 mice at 48 weeks of age. Arrows indicate regions of AT2 cell loss. (B) Schematic to evaluate AT2 cell loss in WT, HPS1, HPS2, and HPS1/2 mice over time. (C) Staining of paraffin-embedded lung tissue for proSP-C in WT, HPS1, HPS2, and HPS1/2 mice at 8 and 48 weeks of age. (D) Quantification of percentage of proSP-C+ cells as a percentage of total cells (by DAPI) in WT, HPS1, HPS2, and HPS1/2 mice at 4, 8, 24, and 48 weeks of age. (E) Schematic of AT2 cell loss in HPS mice and possible etiologies. DAPI stains nuclei (blue). All quantification data are represented as mean ± SEM. Statistics using 2-tailed unpaired Student’s t tests: adjusted * P < 0.05; ** P < 0.01, *** P < 0.001 after Benjamini-Hochberg correction for multiple comparisons. n = 4–6 per group per time point. Scale bars in A, 50 μm; C, 20 μm. Schematics created with BioRender.com.'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/183000/183483/small/jci.insight.183483.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7190-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183483">Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183483">Text</a></li> <li><a class="button tiny" href="/articles/view/183483/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single-mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double-mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell function was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage-tracing and organoid-modeling studies demonstrated that HPS AT2 cells were primed to persist in a Keratin-8–positive reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Joanna Y. Wang, Sylvia N. Michki, Sneha Sitaraman, Brandon J. Banaschewski, Reshma Jamal, Jason J. Gokey, Susan M. Lin, Jeremy B. Katzen, Maria C. Basil, Edward Cantu, Jonathan A. Kropski, Jarod A. Zepp, David B. Frank, Lisa R. Young</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183684">Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183684">Yi Fan, … , Clifford J. Rosen, Chenchen Zhou</a> <a class='hide-for-small show-more' data-reveal-id='article7200-more' href='#'> <div class='article-authors'> Yi Fan, … , Clifford J. Rosen, Chenchen Zhou </div> </a> <span class='article-published-at'> Published December 17, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e183684. <a href="https://doi.org/10.1172/jci.insight.183684">https://doi.org/10.1172/jci.insight.183684</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183684">Text</a> | <a href="/articles/view/183684/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.183684' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/183684/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/183000/183684/small/jci.insight.183684.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7200-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183684">Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183684">Text</a></li> <li><a class="button tiny" href="/articles/view/183684/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Regeneration of orofacial bone defects caused by inflammation-related diseases or trauma remains an unmet challenge. Parathyroid hormone 1 receptor (PTH1R) signaling is a key mediator of bone remodeling whereas the regulatory mechanisms of PTH1R signaling in oral bone under homeostatic or inflammatory conditions have not been demonstrated by direct genetic evidence. Here, we observed that deletion of PTH1R in Gli1+ progenitors led to increased osteogenesis and osteoclastogenesis. Single-cell and bulk RNA-Seq analysis revealed that PTH1R suppressed the osteogenic potential of Gli1+ progenitors during inflammation. Moreover, we identified upregulated IGF1 expression upon PTH1R deletion. Dual deletion of IGF1 and PTH1R ameliorated the bone-remodeling phenotypes in PTH1R-deficient mice. Furthermore, in vivo evidence revealed an inverse relationship between PTH1R and Hedgehog signaling, which was responsible for the upregulated IGF1 production. Our work underscored the negative feedback between PTH1R and IGF1 in craniofacial bone turnover and revealed mechanisms modulating orofacial bone remodeling.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yi Fan, Ping Lyu, Jiahe Wang, Yali Wei, Zucen Li, Shiwen Zhang, Takehito Ouchi, Junjun Jing, Quan Yuan, Clifford J. Rosen, Chenchen Zhou</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184379">Mapping cell diversity and dynamics in inflammatory temporomandibular joint osteoarthritis with pain at single-cell resolution</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184379">Supawadee Jariyasakulroj, … , Pao-Fen Ko, Jian-Fu Chen</a> <a class='hide-for-small show-more' data-reveal-id='article7195-more' href='#'> <div class='article-authors'> Supawadee Jariyasakulroj, … , Pao-Fen Ko, Jian-Fu Chen </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e184379. <a href="https://doi.org/10.1172/jci.insight.184379">https://doi.org/10.1172/jci.insight.184379</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184379">Text</a> | <a href="/articles/view/184379/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.184379' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/184379/figure/1' ref='group' title='TMJ OA-like defects in CFA intra-articular injection mice. (A) Micro-CT of live images of a sagittal view of the mandibular condyle. Scale bar: 500 μm. (B–E) Quantification analysis of microarchitecture parameters of the subchondral bone. Values represent mean ± SD, *P < 0.05, **P < 0.01, ****P < 0.0001 (n = 4 control mice, n = 6 CFA-injected mice). BV/TV, bone volume/total volume; 1/mm, 1 trabecular number per mm region. (F) H&E staining of sagittal TMJ sections. Black dashed boxes indicate the anterior and posterior synovial tissue around the condyle. Scale bar: 500 μm. (G) TMJ synovitis tissue histopathology from boxed regions in F. The TMJ of CFA-injected mice presented features of OA-like defects, including hyperplastic epithelial lining (black arrows in anterior area) and immune cellular infiltration caused by inflammation (black arrows in posterior area). Scale bar: 100 μm. (H and I) Quantification of TMJ synovitis evaluated by Synovitis Scoring System with 2 assessment criteria: synovial hyperplasia (H) and inflammatory infiltrate (I). Values represent mean ± SD. *P < 0.05 (n = 12 sections from 3 control mice, n = 18 sections from 4 CFA-injected mice). (J) Immunofluorescence staining of Cathepsin K (green) in mandibular condyles. Scale bar: 100 μm. (K) Quantification of Cathepsin K+ osteoclast cells in subchondral bone of the TMJ condylar head. Values represent mean ± SD calculated by Student’s t test. n ≥ 3 mice, *P < 0.05. (L) H&E staining of sagittal TMJ condylar cartilage part from sections in F. Arrowheads indicate uneven surface and loss of fibrous layer in the CFA group. Note the unclear borders between cartilage and subchondral bone, uneven cartilage surfaces, and decreased hypertrophic layer thickness in the CFA group. Scale bar: 100 μm. (M) Quantification of Osteoarthritis Research Society International (OARSI) score in TMJs. Data are represented as mean ± SEM calculated by Student’s t test. n ≥ 3 mice, ***P < 0.001.'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/184000/184379/small/jci.insight.184379.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7195-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184379">Mapping cell diversity and dynamics in inflammatory temporomandibular joint osteoarthritis with pain at single-cell resolution</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184379">Text</a></li> <li><a class="button tiny" href="/articles/view/184379/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Temporomandibular joint (TMJ) osteoarthritis with pain is a highly prevalent disorder affecting patients’ quality of life. A comprehensive understanding of cell type diversity and its dynamics in painful TMJ osteoarthritis (TMJOA) is lacking. Here, we utilized an inflammatory TMJOA mouse model via intra-articular injection of CFA. TMJOA mice exhibited cartilage remodeling, bone loss, synovitis, increased osteoarthritis (OA) score, and orofacial pain, recapitulating hallmark symptoms in patients. Single-cell transcriptomic profiling of the TMJ was performed in conjunction with mouse genetic labeling, tissue clearing, light sheet and confocal 3D imaging, multiplex RNAscope, and immunodetection. We visualized, reconstructed, and analyzed the distribution and density of nociceptive innervation of TMJ at single-axon levels. We systematically mapped the heterogeneity and anatomical position of blood endothelial cells, synovial fibroblasts, and immune cells, including Cx3cr1-positive barrier macrophages. Importantly, TMJOA mice exhibited enhanced neurovascular coupling, sublining fibroblast hyperplasia, inflammatory immune cell expansion, disrupted signaling-dependent cell-cell interaction, and a breakdown of the sandwich-like organization consisting of synovial barrier macrophages and fibroblasts. By utilizing a mouse model with combined TMJ pain history and OA, we reveal the cellular diversity, anatomical structure, and cell dynamics of the TMJ at single-cell resolution, which facilitate our understanding and potential targeting of TMJOA.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Supawadee Jariyasakulroj, Yang Shu, Ziying Lin, Jingyi Chen, Qing Chang, Pao-Fen Ko, Jian-Fu Chen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184451">Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184451">Jun Nakamura, … , Andrea Ballabio, Yoshitaka Isaka</a> <a class='hide-for-small show-more' data-reveal-id='article7205-more' href='#'> <div class='article-authors'> Jun Nakamura, … , Andrea Ballabio, Yoshitaka Isaka </div> </a> <span class='article-published-at'> Published December 19, 2024 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e184451. <a href="https://doi.org/10.1172/jci.insight.184451">https://doi.org/10.1172/jci.insight.184451</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184451">Text</a> | <a href="/articles/view/184451/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.184451' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/184451/ga' ref='group' title='Graphical abstract'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/184000/184451/small/jci.insight.184451.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7205-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184451">Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4–related amyloidosis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184451">Text</a></li> <li><a class="button tiny" href="/articles/view/184451/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria–lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186096">Prenatal alcohol exposure is associated with altered feto-placental blood flow and sex-specific placental changes</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186096">Sarah E. Steane, … , Karen M. Moritz, Vicki L. Clifton</a> <a class='hide-for-small show-more' data-reveal-id='article7223-more' href='#'> <div class='article-authors'> Sarah E. Steane, … , Karen M. Moritz, Vicki L. Clifton </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e186096. <a href="https://doi.org/10.1172/jci.insight.186096">https://doi.org/10.1172/jci.insight.186096</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186096">Text</a> | <a href="/articles/view/186096/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.186096' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://insight.jci.org/articles/view/186096/figure/1' ref='group' title='Flow diagram of study. Number of participants enrolled, withdrawals/exclusions, and final number included. Sample sizes for participant data/samples are shown with details of analyses. 5MTHF, 5-methyltetrahydrofolate; SAM, S-adenosylmethionine; PlGF, placental growth factor; VEGFA, vascular endothelial growth factor; FLT1, VEGF receptor 1; KDR, VEGF receptor 2; DNMT, DNA methyltransferase; MTOR, mechanistic target of rapamycin; RFC, reduced folate carrier.'> <img src='//df6sxcketz7bb.cloudfront.net/manuscripts/186000/186096/small/jci.insight.186096.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7223-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186096">Prenatal alcohol exposure is associated with altered feto-placental blood flow and sex-specific placental changes</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186096">Text</a></li> <li><a class="button tiny" href="/articles/view/186096/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Prenatal alcohol exposure (PAE) around conception in preclinical models results in placental insufficiency, likely contributing to offspring abnormalities. Altered placental DNA methylation (DNAm) and gene expression suggest epigenetic mechanisms, perhaps involving impacts on methyl donor levels. PAE around conception in women is common but placental effects are rarely examined. This cohort study investigated associations between PAE around conception and intake/plasma measures of the methyl donors folate and choline, feto-placental blood flow, and placental growth measures, gene expression, and DNAm.METHODS Pregnant participants delivered at Mater Mothers’ Hospital, Brisbane, Queensland, Australia (n = 411). Dietary intake of choline and folate were calculated and plasma concentrations measured using mass spectrometry (MS) and clinical immunoanalyzer, respectively. Cerebroplacental ratio (CPR) was calculated using Doppler measurements. Placentas were weighed/measured at delivery and samples used to quantify methyl donors (MS), global DNAm (ELISA), and gene expression (quantitative PCR). Data were compared between control/abstinent and PAE groups, by fetal sex.RESULTS A CPR <5th-centile, indicating fetal brain sparing because of placental insufficiency, was found in 2% of controls and 18% of the PAE group, mostly male fetuses (63%). Compared with controls, male PAE placentas had reduced mean thickness and placental growth factor mRNA and DNAm, whereas female PAE placentas had increased S-adenosylmethionine and a trend toward increased DNAm.CONCLUSION PAE around conception is associated with reduced CPR and altered placental growth measures, particularly in males, with potential implications for future health.FUNDING National Health and Medical Research Council (APP1191217) and Mary McConnel Career Boost Program for Women in Paediatric Research (WIS132020).</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sarah E. Steane, Christopher Edwards, Erika Cavanagh, Chelsea Vanderpeet, Jade M. Kubler, Lisa K. Akison, James S.M. Cuffe, Linda A. Gallo, Karen M. Moritz, Vicki L. Clifton</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='corrigendum'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel1' name='corrigendum'> <strong></strong> <span class='toggle-icon'></span> Corrigendum </a> <div class='content active' id='panel1'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191787">Longitudinal clinical and proteomic diabetes signatures in women with a history of gestational diabetes</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191787">Heaseung Sophia Chung, … , Agneta Holmäng, Ulrika Andersson-Hall</a> <a class='hide-for-small show-more' data-reveal-id='article7219-more' href='#'> <div class='article-authors'> Heaseung Sophia Chung, … , Agneta Holmäng, Ulrika Andersson-Hall </div> </a> <span class='article-published-at'> Published February 10, 2025 </span> <br/>Citation Information: <i>JCI Insight.</i> 2025;<a id="article_metadata" href="http://insight.jci.org/10/3">10(3)</a>:e191787. <a href="https://doi.org/10.1172/jci.insight.191787">https://doi.org/10.1172/jci.insight.191787</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191787">Text</a> | <a href="/articles/view/191787/pdf">PDF</a> | <a href="/articles/view/183213">Amended Article</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.191787' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7219-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191787">Longitudinal clinical and proteomic diabetes signatures in women with a history of gestational diabetes</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191787">Text</a></li> <li><a class="button tiny" href="/articles/view/191787/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Heaseung Sophia Chung, Lawrence Middleton, Manik Garg, Ventzislava A. Hristova, Rick B. Vega, David Baker, Benjamin G. Challis, Dimitrios Vitsios, Sonja Hess, Kristina Wallenius, Agneta Holmäng, Ulrika Andersson-Hall</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <hr> <h4> In-Press Preview <small>- <a title="View more In-Press Preview articles" href="/in-press-preview">More</a></small> </h4> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185946">Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article7270-more' href='#'> <div class='article-abstract'> Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms... </div> </a> <span class='article-published-at'> Published February 18, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/61"><span class='label-article-type'> Research </span> </a><a href="/tags/59"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/16"><span class='label-specialty'> Cell biology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.185946' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7270-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185946">Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185946">Text</a></li> <li><a class="button tiny" href="/articles/view/185946/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By eight months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 47% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway alterations. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared to non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC cells, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai-Kin Chan, Collene Jeter, Lin Tan, M. Anna Zal, Philip L. Lorenzi, Kenneth Dunner Jr., Richard K. Yang, Russell R. Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Deena M. Scoville, Tae Hoon KIM, Jae-Wook Jeong, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S. Yates</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184935">Complement activation at the interface between adipocytes and cancer cells drives tumor progression</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article7274-more' href='#'> <div class='article-abstract'> The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer... </div> </a> <span class='article-published-at'> Published February 18, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/61"><span class='label-article-type'> Research </span> </a><a href="/tags/59"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/16"><span class='label-specialty'> Cell biology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.184935' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7274-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184935">Complement activation at the interface between adipocytes and cancer cells drives tumor progression</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184935">Text</a></li> <li><a class="button tiny" href="/articles/view/184935/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct co-culture model with immortalized human visceral pre-adipocytes (VNPAD) and OC cells. We demonstrate increased proliferation, invasiveness, and resistance to cisplatin of co-cultured compared to mono-cultured OC cells. RNA-sequencing of OC cells from co-culture vs. mono-culture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes (DEGs) common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and Complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in-vivo. Increased C3 expression was observed in omental implants compared to primary ovarian tumors and C3 secretion was higher in OC ascites from high BMI vs. low BMI patients. C3 upregulation in OC cells involved activation of ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promote invasiveness and tumorigenesis via lipid transfer, activating ISR, and upregulating complement proteins C3 and C5.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Andres Valdivia, Ana Isac, Horacio Cardenas, Guangyuan Zhao, Yaqi Zhang, Hao Huang, Jian-Jun Wei, Mauricio Cuello-Fredes, Sumie Kato, Fernán Gómez-Valenzuela, Francoise A. Gourronc, Aloysius J. Klingelhutz, Daniela Matei</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177072">CD103<sup>+</sup> dendritic cell — fibroblast crosstalk via TLR9, TDO2, and AHR signaling drives lung fibrogenesis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article7275-more' href='#'> <div class='article-abstract'> Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The... </div> </a> <span class='article-published-at'> Published February 18, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/61"><span class='label-article-type'> Research </span> </a><a href="/tags/59"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/36"><span class='label-specialty'> Pulmonology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.177072' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7275-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177072">CD103<sup>+</sup> dendritic cell — fibroblast crosstalk via TLR9, TDO2, and AHR signaling drives lung fibrogenesis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177072">Text</a></li> <li><a class="button tiny" href="/articles/view/177072/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with blm developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2 and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborates the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Hannah Carter, Rita Medina Costa, Taylor S. Adams, Talon M. Gilchrist, Claire E. Emch, Monica Bame, Justin M. Oldham, Steven K. Huang, Angela L. Linderholm, Imre Noth, Naftali Kaminski, Bethany B. Moore, Stephen J. Gurczynski</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185834">Impact of aging on pulmonary cellular responses during mechanical ventilation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article7262-more' href='#'> <div class='article-abstract'> Acute respiratory distress syndrome (ARDS) results in significant morbidity and mortality, especially in the elderly. Mechanical ventilation, a common supportive treatment for ARDS, is necessary... </div> </a> <span class='article-published-at'> Published February 13, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/61"><span class='label-article-type'> Research </span> </a><a href="/tags/59"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/10"><span class='label-specialty'> Aging </span> </a><a href="/tags/36"><span class='label-specialty'> Pulmonology </span> </a><a href="/tags/42"><span class='label-specialty'> Vascular biology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.185834' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7262-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185834">Impact of aging on pulmonary cellular responses during mechanical ventilation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185834">Text</a></li> <li><a class="button tiny" href="/articles/view/185834/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Acute respiratory distress syndrome (ARDS) results in significant morbidity and mortality, especially in the elderly. Mechanical ventilation, a common supportive treatment for ARDS, is necessary for maintaining gas exchange, but can also propagate injury. We hypothesized that aging leads to alterations in surfactant function, inflammatory signaling, and microvascular permeability within the lung during mechanical ventilation. Young and aged male mice were mechanically ventilated, and surfactant function, inflammation, and vascular permeability were assessed. Additionally, single-cell RNA sequencing was used to delineate cell-specific transcriptional changes. The results showed that in aged mice, surfactant dysfunction and vascular permeability were significantly augmented, while inflammation was less pronounced. Differential gene expression and pathway analyses revealed that alveolar macrophages in aged mice showed a blunted inflammatory response, while aged endothelial cells exhibited altered cell-cell junction formation. In vitro functional analysis revealed that aged endothelial cells had an impaired ability to form a barrier. These results highlight the complex interplay between aging and mechanical ventilation, including an age-related predisposition to endothelial barrier dysfunction, due to altered cell-cell junction formation, and decreased inflammation, potentially due to immune exhaustion. It is concluded that age-related vascular changes may underlie the increased susceptibility to injury during mechanical ventilation in elderly patients.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Aminmohamed Manji, Lefeng Wang, Cynthia M. Pape, Lynda A. McCaig, Alexandra Troitskaya, Onon Batnyam, Leah J.J. McDonald, C. Thomas Appleton, Ruud A.W. Veldhuizen, Sean E. Gill</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180229">Quinolinic acid potentially links kidney injury to brain toxicity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article7264-more' href='#'> <div class='article-abstract'> Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid... </div> </a> <span class='article-published-at'> Published February 13, 2025 </span> <div class='row'> <div class='small-12 columns article-links'> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/61"><span class='label-article-type'> Research </span> </a><a href="/tags/59"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/31"><span class='label-specialty'> Nephrology </span> </a><a href="/tags/32"><span class='label-specialty'> Neuroscience </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/jci.insight.180229' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article7264-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180229">Quinolinic acid potentially links kidney injury to brain toxicity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180229">Text</a></li> <li><a class="button tiny" href="/articles/view/180229/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by Mdm2 conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced CKD (stage 3B-4, n = 18 and stage 5, n = 8), similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Afaf Saliba, Subrata Debnath, Ian Tamayo, Hak Joo Lee, Nagarjunachary Ragi, Falguni Das, Richard Montellano, Jana Tumova, Meyer Maddox, Esmeralda Trevino, Pragya Singh, Caitlyn Fastenau, Soumya Maity, Guanshi Zhang, Leila Hejazi, Manjeri A. Venkatachalam, Jason C. O'Connor, Bernard Fongang, Sarah C. Hopp, Kevin F. Bieniek, James D. Lechleiter, Kumar Sharma</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row panel-padding'> <div class='small-12 columns'> <h5>View more articles by topic:</h5> </div> <div class='small-12 columns'> <div class='row'> <div class='large-4 columns'> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/10">Aging</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/11">AIDS/HIV</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/12">Angiogenesis</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/14">Bone biology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/15">Cardiology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/16">Cell biology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/17">Clinical trials</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/64">COVID-19</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/18">Dermatology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/19">Development</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/20">Endocrinology</a></p> </div> </div> </div> <div class='large-4 columns'> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/21">Gastroenterology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/22">Genetics</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/23">Hematology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/24">Hepatology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/25">Immunology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/26">Infectious disease</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/27">Inflammation</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/28">Metabolism</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/29">Microbiology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/30">Muscle biology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/31">Nephrology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/32">Neuroscience</a></p> </div> </div> </div> <div class='large-4 columns'> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/33">Oncology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/34">Ophthalmology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/35">Otology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/36">Pulmonology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/37">Reproductive biology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/38">Stem cells</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/39">Therapeutics</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/40">Transplantation</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/41">Vaccines</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/42">Vascular biology</a></p> </div> </div> <div class='row'> <div class='small-12 columns'> <p><a href="/tags/43">Virology</a></p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class='large-4 large-pull-8 medium-5 medium-pull-7 columns'> <div class='row homepage-panel centered' id='insight-homepage-med-rectangle-left-col-top'> <div class='small-12 columns'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('insight-homepage-med-rectangle-left-col-top'); 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