The Journal of Clinical Investigation最新文献

{"title":"TFIIH-p52∆C defines a ninth xeroderma pigmentosum complementation-group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy.","authors":"Yuka Nakazawa,Lin Ye,Yasuyoshi Oka,Hironobu Morinaga,Kana Kato,Mayuko Shimada,Kotaro Tsukada,Koyo Tsujikawa,Yosuke Nishio,Hiva Fassihi,Shehla Mohammed,Alan R Lehmann,Tomoo Ogi","doi":"10.1172/jci195732","DOIUrl":"https://doi.org/10.1172/jci195732","url":null,"abstract":"Few drugs are available for rare diseases due to economic disincentives. However, tailored medications for extremely-rare disorders (N-of-1) offer a ray of hope. Artificial antisense oligonucleotides (ASOs) are now best known for their use in spinal muscular atrophy (SMA). The success of nusinersen/Spinraza for SMA indicates ASO-therapies' potential for other rare conditions. We propose a strategy to develop N-of-1 ASOs for treating one form of trichothiodystrophy (TTD), a rare condition with multisystem abnormalities and reduced life expectancy, associated with instability and greatly reduced amounts of the DNA-repair/transcription factor TFIIH. The therapeutic target carry mutations in GTF2H5, encoding the TFIIH-p8 subunit. This approach was inspired by the diagnosis and molecular dissection of a xeroderma pigmentosum (XP) case with mutations in GTF2H4, encoding the TFIIH-p52 subunit. This is newly classified as a ninth XP complementation-group, XP-J, identified five decades after the discovery of the other XP complementation-groups. The p8-p52 interaction is required to support the TFIIH-complex formation, and the patient's p52 C-terminal truncation results in the complete absence of p8 in TFIIH. However, intriguingly, TFIIH remained stable in vivo, and the XP-J patient did not exhibit any TTD-features. The aim of our ASO-design is to induce a C-terminal truncation of p52 and we have successfully stabilised TFIIH in p8-deficient TTD-A patient cells.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-omics recovery factor predicts long COVID in the IMPACC study.","authors":"Gisela Gabernet,Jessica Maciuch,Jeremy P Gygi,John F Moore,Annmarie Hoch,Caitlin Syphurs,Tianyi Chu,Naresh Doni Jayavelu,David B Corry,Farrah Kheradmand,Lindsey R Baden,Rafick-Pierre Sekaly,Grace A McComsey,Elias K Haddad,Charles B Cairns,Nadine Rouphael,Ana Fernandez-Sesma,Viviana Simon,Jordan P Metcalf,Nelson I Agudelo Higuita,Catherine L Hough,William B Messer,Mark M Davis,Kari C Nadeau,Bali Pulendran,Monica Kraft,Chris Bime,Elaine F Reed,Joanna Schaenman,David J Erle,Carolyn S Calfee,Mark A Atkinson,Scott C Brakenridge,Esther Melamed,Albert C Shaw,David A Hafler,Alison D Augustine,Patrice M Becker,Al Ozonoff,Steven E Bosinger,Walter Eckalbar,Holden T Maecker,Seunghee Kim-Schulze,Hanno Steen,Florian Krammer,Kerstin Westendorf,Impacc Network,Bjoern Peters,Slim Fourati,Matthew C Altman,Ofer Levy,Kinga K Smolen,Ruth R Montgomery,Joann Diray-Arce,Steven H Kleinstein,Leying Guan,Lauren Ir Ehrlich","doi":"10.1172/jci193698","DOIUrl":"https://doi.org/10.1172/jci193698","url":null,"abstract":"BACKGROUNDFollowing SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which debilitating symptoms persist for at least three months. Elucidating biologic underpinnings of LC could identify therapeutic opportunities.METHODSWe utilized machine learning methods on biologic analytes provided over 12-months after hospital discharge from >500 COVID-19 patients in the IMPACC cohort to identify a multi-omics \"recovery factor\", trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood CyTOF protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.RESULTSLC participants had lower recovery factor scores compared to recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.CONCLUSIONThe multi-omics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.TRIAL REGISTRATIONCLINICALTRIALSgov NCT04378777.FUNDINGThis study was funded by NIH, NIAID and NSF.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZEB1 promotes chemo-immune resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16.","authors":"Shaobo Zhang,Yumeng Hu,Zhijun Zhou,Gaoyuan Lv,Chenze Zhang,Yuanyuan Guo,Fangxia Wang,Yuxin Ye,Haoran Qi,Hui Zhang,Wenming Wu,Min Li,Mingyang Liu","doi":"10.1172/jci195970","DOIUrl":"https://doi.org/10.1172/jci195970","url":null,"abstract":"Pancreatic cancer (PC) is notoriously resistant to both chemotherapy and immunotherapy, presenting a major therapeutic challenge. Epigenetic modifications play a critical role in PC progression, yet their contribution to chemoimmunotherapy resistance remains poorly understood. Here, we identified the transcription factor ZEB1 as a critical driver of chemoimmunotherapy resistance in PC. ZEB1 knockdown synergized with gemcitabine and anti-PD1 therapy, markedly suppressed PC growth, and prolonged survival in vivo. Single-cell and spatial transcriptomics revealed that ZEB1 ablation promoted tumor pyroptosis by recruiting and activating GZMA+CD8+ T cells in the tumor core through epigenetic upregulation of CXCL16. Meanwhile, ZEB1 blockade attenuates CD44+ neutrophil-induced CD8+ T cell exhaustion by reducing tumor-derived SPP1 secretion, which otherwise promotes exhaustion through activation of the PD-L1-PD-1 pathway. Clinically, high ZEB1 expression correlated with chemoresistance, immunosuppression, and diminished CXCL16 levels in PC patients. Importantly, the epigenetic inhibitor Mocetinostat (targeting ZEB1) potentiated chemoimmunotherapy efficacy, including anti-PD1 and CAR-T therapies, in patient-derived organoids, xenografts, and orthotopic models. Our study unveils ZEB1 as a master epigenetic regulator of chemoimmunotherapy resistance and proposes its targeting as a transformative strategy for PC treatment.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.","authors":"Rui Guo,Yizhe Sun,Matthew Y Lim,Hardik Shah,Joao A Paulo,Rahaman A Ahmed,Weixing Li,Yuchen Zhang,Haopeng Yang,Liang Wei Wang,Daniel Strebinger,Nicholas A Smith,Meng Li,Merrin Man Long Leong,Michael Lutchenkov,Jin-Hua Liang,Zhixuan Li,Yin Wang,Rishi Puri,Ari Melnick,Michael R Green,John M Asara,Adonia E Papathanassiu,Duane R Wesemann,Steven P Gygi,Vamsi K Mootha,Benjamin E Gewurz","doi":"10.1172/jci186258","DOIUrl":"https://doi.org/10.1172/jci186258","url":null,"abstract":"B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states highly induced the transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mechanistic target of rapamycin complex 1 (mTORC1) activation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes and identify BCAT1 as an activated B-cell therapeutic target.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cell quantification of in situ inflammation partitions human lupus nephritis into mechanistic subtypes.","authors":"Gabriel Casella,Madeleine S Torcasso,Junting Ai,Thao P Cao,Satoshi Hara,Michael S Andrade,Deepjyoti Ghosh,Daming Shao,Anthony Chang,Kichul Ko,Anita S Chong,Maryellen L Giger,Marcus R Clark","doi":"10.1172/jci192669","DOIUrl":"https://doi.org/10.1172/jci192669","url":null,"abstract":"BACKGROUNDIn human lupus nephritis (LuN), tubulointerstitial inflammation (TII) is prognostically more important than glomerular inflammation. However, a comprehensive understanding of both TII complexity and heterogeneity is lacking.METHODSHerein, we used high-dimensional confocal microscopy, spatial transcriptomics and specialized computer vision techniques to quantify immune cell populations and localize these within normal and diseased renal cortex structures. With these tools, we compared LuN to renal allograft rejection (RAR) and normal kidney on 54 de-identified biopsies.RESULTSIn both LuN and RAR, the 33 characterized immune cell populations formed discrete subgroups whose constituents co-varied in prevalence across biopsies. In both diseases, these co-variant immune cell subgroups organized into the same unique niches. Therefore, inflammation could be resolved into trajectories representing the relative prevalence and density of cardinal immune cell members of each co-variant subgroup. Indeed, in any one biopsy, the inflammatory state could be characterized by quantifying constituent immune cell trajectories. Remarkably, LuN heterogeneity could be captured by quantifying a few myeloid immune cell trajectories while RAR was more complex with additional T cell trajectories.CONCLUSIONSOur studies identify rules governing renal inflammation and thus provide an approach for resolving LuN into discrete mechanistic categories.FUNDINGNIH (U19 AI 082724 [MRC], R01 AI148705 [MRC and ASC]), Chan Zuckerberg Biohub (MRC) and Lupus Research Alliance (MRC).","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice.","authors":"Ge Dong,Jingjing Liu,Wenyan Jin,Hongxi Zhou,Yuchen Wen,Zhiqin Wang,Keyao Xia,Jianlin Zhang,Linxiang Ma,Yunxi Ma,Lorie Chen Cai,Qiufan Zhou,Huaquan Wang,Wei Wei,Ying Fu,Zhigang Cai","doi":"10.1172/jci193011","DOIUrl":"https://doi.org/10.1172/jci193011","url":null,"abstract":"VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that murine mutants with about 70% loss of Uba1 in neutrophils induced non-lethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss while depletion of Uba1 in B or T cells, or in megakaryocytes induced corresponsive cell death but these mutants appeared normal. Depletion of Uba1 in monocytes and neutrophils failed to induce cell death and the mutants were viable. Among the tested models, only depletion of Uba1 in neutrophils induced autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, occurrence of vacuoles in myeloid cells, splenomegaly and dermatitis. Residual Uba1 was about 30% in the mutant neutrophils, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will assist understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ppp2r1a haploinsufficiency increases excitatory synaptic transmission and decreases spatial learning by impairing endocannabinoid signaling.","authors":"Yirong Wang,Weicheng Duan,Hua Li,Zhiwei Tang,Ruyi Cai,Shangxuan Cai,Guanghao Deng,Liangpei Chen,Hongyan Luo,Liping Chen,Yulong Li,Jian-Zhi Wang,Bo Xiong,Man Jiang","doi":"10.1172/jci185602","DOIUrl":"https://doi.org/10.1172/jci185602","url":null,"abstract":"Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase in the brain. Mutations in PPP2R1A, encoding the scaffolding subunit, are linked to intellectual disability, although the underlying mechanisms remain unclear. This study examined mice with heterozygous deletion of Ppp2r1a in forebrain excitatory neurons (NEX-het-conditional knockout [NEX-het-cKO]). These mice exhibited impaired spatial learning and memory, resembling Ppp2r1a-associated intellectual disability. Ppp2r1a haploinsufficiency also led to increased excitatory synaptic strength and reduced inhibitory synapse numbers on pyramidal neurons. The increased excitatory synaptic transmission was attributed to increased presynaptic release probability, likely due to reduced levels of 2-arachidonoyl glycerol (2-AG). This reduction in 2-AG was associated with increased transcription of monoacylglycerol lipase (MAGL), driven by destabilization of enhancer of zeste homolog 2 (EZH2) in NEX-het-cKO mice. Importantly, the MAGL inhibitor JZL184 effectively restored both synaptic and learning deficits. Our findings uncover an unexpected role of PPP2R1A in regulating endocannabinoid signaling, providing fresh molecular and synaptic insights into the mechanisms underlying intellectual disability.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual targeting CDK4/6 and CDK7 augments tumor response and anti-tumor immunity in breast cancer models.","authors":"Sungsoo Kim,Eugene Son,Ha-Ram Park,Minah Kim,Hee Won Yang","doi":"10.1172/jci188839","DOIUrl":"https://doi.org/10.1172/jci188839","url":null,"abstract":"Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for hormone receptor-positive (HR+) breast cancer. However, their long-term efficacy is limited by acquired resistance, and CDK4/6i monotherapy remains ineffective in triple-negative breast cancer (TNBC). Here, we demonstrate that dual inhibition of CDK4/6 and CDK7 is a promising strategy to overcome therapeutic resistance in both HR+ and TNBC models. Kinetic analyses reveal that CDK7 inhibitors (CDK7i) primarily impair RNA polymerase II-mediated transcription rather than directly targeting cell-cycle CDKs. This transcriptional suppression attenuates E2F-driven transcriptional amplification, a key mechanism for developing CDK4/6i resistance following the degradation of the retinoblastoma protein. Consequently, combining CDK7i at minimal effective concentrations with CDK4/6i potently inhibits the growth of drug-resistant tumors. Furthermore, dual CDK4/6 and CDK7 inhibition stimulates immune-related signaling and cytokine production in cancer cells, promoting anti-tumor immune responses within the tumor microenvironment. These findings provide mechanistic insights into CDK inhibition and support the therapeutic potential of combining CDK7i with CDK4/6i for breast cancer treatment.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression.","authors":"Rachel J Stapley,Xenia Sawkulycz,Gabriel Hm Da Mota Araujo,Maximilian Englert,Lourdes Garcia-Quintanilla,Sophie Rm Smith,Amna Ahmed,Elizabeth J Haining,Nayandeep Kaur,Andrea Bacon,Andrey V Pisarev,Natalie S Poulter,Dean Pj Kavanagh,Steven G Thomas,Samantha J Montague,Julie Rayes,Zoltan Nagy,Neil V Morgan","doi":"10.1172/jci189100","DOIUrl":"https://doi.org/10.1172/jci189100","url":null,"abstract":"SLFN14-related thrombocytopenia is a rare bleeding disorder caused by SLFN14 mutations altering hemostasis in patients with platelet dysfunction. Schlafen (SLFN) proteins are highly conserved in mammals where SLFN14 is specifically expressed in megakaryocyte (MK) and erythroblast lineages. The role of SLFN14 in megakaryopoiesis and platelet function has not been elucidated. We generated a new murine model with a platelet- and MK-specific SLFN14 deletion using platelet factor-4 (PF4) cre-mediated deletion of exons 2 and 3 in Slfn14 (Slfn14;PF4-Cre) to decipher the molecular mechanisms driving the bleeding phenotype. SLFN14;PF4-Cre+ platelets displayed reduced platelet signaling to thrombin, reduced thrombin formation, increased bleeding tendency, and delayed thrombus formation as assessed by intravital imaging. Moreover, fewer in situ bone marrow MKs compared to controls. RNA sequencing and gene ontology analysis of MKs and platelets from Slfn14;PF4-Cre homozygous mice revealed altered pathways of ubiquitination, ATP activity, cytoskeleton and molecular function. In summary, we investigated how SLFN14 deletion in MKs and platelets leads to platelet dysfunction and alters their transcriptome, explaining the platelet dysfunction and bleeding in humans and mice with SLFN14 mutations.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TET3 is a common epigenetic immunomodulator of pathogenic macrophages.","authors":"Beibei Liu,Yangyang Dai,Zixin Wang,Jiahui Song,Yushu Du,Haining Lv,Stefania Bellone,Yang-Hartwich Yang,Andrew Kennedy,Songying Zhang,Muthukumaran Venkatachalapathy,Yulia V Surovtseva,Penghua Wang,Gordon G Carmichael,Hugh S Taylor,Xuchen Zhang,Da Li,Yingqun Huang","doi":"10.1172/jci194879","DOIUrl":"https://doi.org/10.1172/jci194879","url":null,"abstract":"Through a combination of single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by TET3 overexpression (Toe-Macs) in three major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enables their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 knockout markedly mitigates disease progression and the therapeutic effects are recapitulated pharmacologically using a TET3-specific small molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulates expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}