JCI insight最新文献

{"title":"The distal nephron biomarkers associate with diabetic kidney disease progression.","authors":"Christina L Tamargo, Steven G Coca, Heather Thiessen Philbrook, David G Hu, Joachim H Ix, Michael G Shlipak, Linda F Fried, Orlando M Gutierrez, Sushrut S Waikar, Sarah J Schrauben, Jeffrey R Schelling, Peter Ganz, Paul L Kimmel, Jason H Greenberg, Rajat Deo, Ayumi Takakura, Ramachandran S Vasan, Joseph V Bonventre, Chirag R Parikh","doi":"10.1172/jci.insight.186836","DOIUrl":"10.1172/jci.insight.186836","url":null,"abstract":"<p><p>BACKGROUNDWhile urinary biomarkers show promise in predicting diabetic kidney disease (DKD) progression, distal tubular markers remain understudied. We investigated the association of distal tubule markers, epidermal growth factor (EGF) and uromodulin (UMOD), with DKD progression in the Veterans Affairs Diabetes in Nephropathy (VA NEPHRON-D) clinical trial.</p><p><strong>Methods: </strong>We used Cox regression models to evaluate the association between each biomarker and DKD progression and the relationship between change over time in biomarker and DKD progression. We used mixed models to investigate biomarker levels at baseline, 12 months, and over time and their relationships with longitudinal eGFR change.</p><p><strong>Results: </strong>Participants (n = 1,116) had type 2 diabetes, urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g, and eGFR 30-89.9 mL/min/1.73 m2. Mean age was 65 years, mean eGFR was 56 (SD 19) mL/min/1.73 m2, and median UACR was 840 (IQR 424-1,780) mg/g. One hundred forty-four participants (13%) had DKD progression over a median follow-up of 2.2 (1.3-3.1) years. Higher baseline EGF and UMOD were independently associated with a lower risk of DKD progression (adjusted HR 0.68, 95% CI 0.47, 0.99 and 0.85, [0.75, 0.98] per 2-fold higher concentration of EGF and UMOD, respectively). Serial biomarker measurements were performed at baseline and 12 months, and a slower decline in biomarkers was associated with a lower risk of DKD progression when adjusted for baseline biomarker levels.</p><p><strong>Conclusion: </strong>Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD.</p><p><strong>Trial registration: </strong></p><p><strong>Clinicaltrials: </strong>gov NCT00555217.</p><p><strong>Funding: </strong>NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic profiling of human adiposomes identifies specific lipid shifts linked to obesity and cardiometabolic risk.","authors":"Abeer M Mahmoud, Imaduddin Mirza, Elsayed Metwally, Mohammed H Morsy, Giorgia Scichilone, Monica C Asada, Amro Mostafa, Francesco M Bianco, Mohamed M Ali, Mario A Masrur, Chandra Hassan, Brian T Layden","doi":"10.1172/jci.insight.191872","DOIUrl":"https://doi.org/10.1172/jci.insight.191872","url":null,"abstract":"<p><p>BACKGROUNDObesity, a growing health concern, often leads to metabolic disturbances, systemic inflammation, and vascular dysfunction. Emerging evidence suggests that adipose tissue-derived extracellular vesicles (adiposomes) may propagate obesity-related complications. However, their lipid composition and effect on cardiometabolic state remain unclear.METHODSThis study examined the lipid composition of adiposomes in 122 participants (75 in obesity group, 47 in lean group) and its connection to cardiometabolic risk. Adiposomes were isolated via ultracentrifugation and characterized using nanoparticle tracking and comprehensive lipidomic analysis by mass spectrometry. Cardiometabolic assessments included anthropometry, body composition, glucose-insulin homeostasis, lipid profiles, inflammatory markers, and vascular function.RESULTSCompared with lean controls, individuals with obesity exhibited elevated adiposome release and shifts in lipid composition, including higher ceramides, free fatty acids, and acylcarnitines, along with reduced levels of phospholipids and sphingomyelins. These alterations strongly correlated with increased BMI, insulin resistance, systemic inflammation, and impaired vascular function. Pathway enrichment analyses highlight dysregulation in glycerophospholipid and sphingolipid metabolism, bile secretion, proinflammatory pathways, and vascular contractility. Machine-learning models utilizing adiposome lipid data accurately classified obesity and predicted cardiometabolic conditions, such as diabetes, hypertension, dyslipidemia, and liver steatosis, achieving accuracy above 85%.CONCLUSIONObesity profoundly remodels the adiposome lipid landscape, linking lipid changes to inflammation, metabolic dysfunction, and vascular impairment. These findings underscore adiposome lipids as biomarkers for obesity and related cardiometabolic disorders, supporting personalized interventions and offering therapeutic value in risk stratification and treatment.FUNDINGThis project was supported by NIH grants R01HL161386, R00HL140049, P30DK020595 (PI: AMM), R01DK104927, and P30DK020595 as well as by a VA Merit Award (1I01BX003382, PI: BTL).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction of Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice.","authors":"Jianqiang Bao, Carlos J Perez, Jeesun Kim, Huan Zhang, Caitlin J Murphy, Tewfik Hamidi, Jean Jaubert, Craig D Platt, Janet Chou, Meichun Deng, Meng-Hua Zhou, Yuying Huang, Héctor Gaitán-Peñas, Jean-Louis Guénet, Kevin Lin, Yue Lu, Taiping Chen, Mark T Bedford, Sharon Yr Dent, John H Richburg, Raúl Estévez, Hui-Lin Pan, Raif S Geha, Qinghua Shi, Fernando Benavides","doi":"10.1172/jci.insight.195729","DOIUrl":"https://doi.org/10.1172/jci.insight.195729","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy.","authors":"Madoka Iida, Kentaro Sahashi, Tomoki Hirunagi, Kenji Sakakibara, Kentaro Maeda, Yohei Iguchi, Jiayi Li, Yosuke Ogura, Masaki Iizuka, Tomohiro Akashi, Kunihiko Hinohara, Shouta Sugio, Hiroaki Wake, Masahiro Nakatochi, Masahisa Katsuno","doi":"10.1172/jci.insight.182123","DOIUrl":"10.1172/jci.insight.182123","url":null,"abstract":"<p><p>Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. To elucidate the cell type-specific temporal gene expression in SBMA, we performed single-nucleus RNA sequencing on the spinal cords of an SBMA mouse model (AR-97Q). Among all cell types, oligodendrocytes had the highest number of differentially expressed genes before disease onset. Analysis of oligodendrocyte clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from oligodendrocytes to neurons in AR-97Q mice compared with wild-type mice. These changes in the early stages were abrogated at the advanced stages. An oligodendrocyte model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization, and Ca2+ imaging of oligodendrocytes in AR-97Q mice revealed the increased Ca2+ responses. A coculture system of primary rat oligodendrocytes and neurons revealed that the mutant AR in oligodendrocytes affected the activity and synchronization of neurons. These findings suggest that dysregulated cell-to-cell communication plays a critical role in early SBMA pathology and that synaptic or ion channel-related proteins, such as contactin associated protein 2 (Cntnap2) and NALCN channel auxiliary factor 1 (Fam155a), are potential therapeutic targets for SBMA.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 12","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment with Efavirenz extends survival in Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.","authors":"Tahir Ali, Jessica Cashion, Samia Hannaoui, Hanaa Ahmed-Hassan, Hermann M Schatzl, Sabine Gilch","doi":"10.1172/jci.insight.190296","DOIUrl":"10.1172/jci.insight.190296","url":null,"abstract":"<p><p>Prion diseases are fatal, infectious and incurable neurodegenerative conditions affecting humans and animals, caused by the misfolding of the cellular prion protein (PrPC) into its pathogenic isoform, PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form. Recently, we demonstrated that treatment with the FDA-approved anti-HIV drug Efavirenz (EFV) significantly reduced PrPSc and extended survival of scrapie prion-infected mice. Among other effects, EFV activates the brain cholesterol metabolizing enzyme, CYP46A1, which converts cholesterol into 24S-hydroxycholesterol (24S-HC). However, drugs effective against scrapie prions often fail in human prion diseases, and a relation of the anti-prion effects of EFV to CYP46A1 activation is not established. Thus, we evaluated EFV treatment in mice overexpressing human PrPC infected with human sCJD prions. Oral, low-dose EFV treatment starting at 30- or 130-days post-infection significantly slowed disease progression and extended their survival. At early clinical stage, we observed reduced PrPSc accumulation, decreased cholesterol and lipid droplet content, and elevated CYP46A1 and 24S-HC levels in EFV-treated mice. Overexpression of CYP46A1 in prion-infected neuronal cells reduced PrPSc levels and increased 24S-HC, indicating that anti-prion effects of EFV correlate with CYP46A1 activation. These findings highlight EFV as a safe and efficacious therapeutic candidate for human prion diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine mapping of heterozygous IL6ST nonsense variants underlying autosomal dominant hyper-IgE syndrome.","authors":"Kosuke Ashihara, Takaki Asano, Kanako Takeuchi, Kosuke Noma, Miyuki Tsumura, Wenjie Wang, Wei-Te Lei, Hisao Higo, Toshio Kubo, Yoko Mizoguchi, Shuhei Karakawa, Aurélie Cobat, Clément Conil, Etsushi Toyofuku, Akimasa Sekine, Kohsuke Imai, Dusan Bogunovic, Jean-Laurent Casanova, Cheng-Lung Ku, Vivien Béziat, Satoshi Okada","doi":"10.1172/jci.insight.190065","DOIUrl":"https://doi.org/10.1172/jci.insight.190065","url":null,"abstract":"<p><p>Loss-of-function (LOF) variants in IL6ST, encoding GP130, can cause hyper-IgE syndrome (HIES). Monoallelic LOF variants in IL6ST lead to HIES when located in the intracellular domain downstream of box 1/2 and upstream of the STAT3 phosphorylation sites and the recycling motif, due to their dominant negative (DN) activity. In this region, two previously unreported IL6ST variants, p.K702Sfs7* and p.Y759Wfs26*, were identified in two families with autosomal dominant (AD) HIES. Both variants were LOF, exhibited DN effects, leading to the accumulation of mutant GP130 on the cell surface. The p.K702Sfs7* mutation was the most upstream N-terminal mutation linked to HIES caused by heterozygous IL6ST variants. Comprehensive screening of IL6ST mutants revealed that most premature terminations downstream of amino acid F641, at the end of the transmembrane domain, resulted in LOF and DN effects via GP130 accumulation on the cell surface. The absence of the recycling motif (positions 782-787) in surface-expressed LOF GP130 led to its accumulation, contributing to the DN effect. The importance of intracellular truncating IL6ST variants can possibly be predicted based on the location of the premature stop codon. GP130 accumulation on the cell surface is a characteristic and potentially diagnostic finding in HIES patients with heterozygous IL6ST variants.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of hypoxia-inducible factor HIF1A as a therapeutic target during SARS-CoV-2-associated lung injury.","authors":"Bentley Bobrow, Samuel D Luber, Paul Potnuru, Katherine Figarella, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B Sergot, Steven K Burke, Tingting Mills, Constanza de Dios, Robert Suchting, George W Williams, Adit A Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I Sessler, Xiaoyi Yuan, Holger K Eltzschig","doi":"10.1172/jci.insight.191463","DOIUrl":"https://doi.org/10.1172/jci.insight.191463","url":null,"abstract":"<p><p>Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We therefore tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF-stabilizer vadadustat. Subsequent studies in genetic models implicated alveolar-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase 2 trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n=448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the two groups. Vadadustat treatment induced surrogate HIF-target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline FiO2 ≥ 80% (n=106), the estimated probability of the primary outcome was 12.1% (vadadustat) vs. 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2-associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MUC5B promoter variant results in proteomic changes in the non-fibrotic lung.","authors":"Jeremy A Herrera, Mark Maslanka, Rachel Z Blumhagen, Rachel Blomberg, Nyan Ye Lwin, Janna Brancato, Carlyne D Cool, Jonathan P Huber, Jonathan S Kurche, Chelsea M Magin, Kirk C Hansen, Ivana V Yang, David A Schwartz","doi":"10.1172/jci.insight.189636","DOIUrl":"https://doi.org/10.1172/jci.insight.189636","url":null,"abstract":"<p><p>The gain-of-function MUC5B promoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both non-fibrotic control and IPF lung specimens have not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry (LCM-MS), we investigated the proteomic profiles of airway and alveolar epithelium in non-fibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the MUC5B promoter variant. Through qualitative and quantitative analyses, as well as pathway analysis and immunohistological validation, we have identified a distinct MUC5B-associated protein profile. Notably, the non-fibrotic control alveoli exhibited substantial MUC5B-associated protein changes, with an increase of IL-3 signaling. Additionally, we found that epithelial cells overlying IPF fibroblastic foci cluster closely to alveolar epithelia and express proteins associated with cellular stress pathways. In conclusion, our findings suggest that the MUC5B promoter variant leads to protein changes in alveolar and airway epithelium that appears to be associated with initiation and progression of lung fibrosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale survey, animal models and computational modeling identify histological neurodegenerative biomarkers for traumatic optic neuropathy.","authors":"YiKui Zhang, BoYue Xu, ShiWei Huang, ZhaoHui Shi, Wei Xiong, Ruijun Wang, GuiQin Liu, Linlin Chen, ZhenHua Ge, YongJie Zhang, HongLei Liu, BaoYun Jia, Chunxia Wang, HaiHong Shi, Jun Kang, NingYu An, Shuirui Huang, De-Fu Chen, Shenghai Huang, YuTing Luo, MingYue Liu, ZhuoWei Wang, Zhonghao Yu, Jingwei Zheng, Wentao Yan, Gen Li, Hao Chen, XingGuang Deng, Shihui Wei, YunHai Tu, EnDe Wu, Kang Zhang, Wencan Wu","doi":"10.1172/jci.insight.190682","DOIUrl":"https://doi.org/10.1172/jci.insight.190682","url":null,"abstract":"<p><strong>Background: </strong>Traumatic optic neuropathy (TON) is a leading cause of blindness following closed traumatic brain injury, with no effective treatments available. Previous interventional clinical trials were complicated by its low prevalence, variability in neurodegenerative severity, and unavailability of reliable biomarkers.</p><p><strong>Methods: </strong>We analyzed data from 1226 patients enrolled in the prospective National Multi-Center Collaborative Clinical Research Program of China (2017-2024) to establish a clinical profile and identify non-invasive biomarkers for neurodegenerative severity. Subgroup analysis of monocular TON patients revealed potential biomarkers including visual functional parameters, inner retinal thickness, and time post-injury.</p><p><strong>Results: </strong>The ganglion cell complex (GCC) thickness showed a strong correlation with retinal ganglion cell somata (R² = 0.87, p < .0001) and axon density (R² = 0.89, p < .0001) in a clinically relevant large animal model. Computational analysis demonstrated that using GCC thickness as a biomarker could substantially enhance the statistical power of clinical trials (by up to 4.5-fold), as confirmed by real-world data.</p><p><strong>Conclusion: </strong>This study presented the largest epidemiological analysis of TON to date and established GCC thickness as a crucial biomarker for stratifying disease severity and improving the efficiency of clinical trials.</p><p><strong>Trial registration: </strong>Chinese Clinical Trial Registry (ChiCTR-OOC-17013437).</p><p><strong>Funding: </strong>National Key R&D Program of China (Grant No.2022YFA1105500); Key Science and Technology Program of Wenzhou (Grant No.ZY2022021); National Natural Science Foundation of China (Grant No.82471080).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy.","authors":"Tianming You, Mehrdad Zandigohar, Tanvi Potluri, Natalie Piehl, John S Coon V, Elizabeth Baker, Maya Kafali, Yang Dai, Jonah J Stulberg, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun","doi":"10.1172/jci.insight.193208","DOIUrl":"https://doi.org/10.1172/jci.insight.193208","url":null,"abstract":"<p><p>More than one in four men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor alpha in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of existing hernias. Addition of progesterone to estradiol treatment was essential for early-onset development of LAM fibrosis and large hernias in wild type mice, which was averted by a progesterone antagonist. Single-nuclei multiomics sequencing of herniated LAM revealed a unique population of Pgr-expressing fibroblasts that promotes fibrosis and myofiber atrophy through transforming growth factor beta-2 signaling. Multiomics findings were validated in vivo in herniated LAM tissues of both mice and adult men. Our findings suggest an important and rare pathologic role of progesterone signaling in males and provide evidence for progesterone antagonists as a non-surgical alternative for inguinal hernia management.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}