The Journal of Clinical Investigation最新文献

Keratinocyte-neutrophil interactions revealed as targetable drivers of sustained inflammation in Sweet syndrome. 角化细胞-中性粒细胞相互作用揭示了Sweet综合征中持续炎症的可靶向驱动因素。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci198494

Umi Tahara,Masayuki Amagai

引用次数: 0

Staphylococcus aureus accessory gene regulator quorum-sensing system inhibits keratinocyte lipid enzymes and delays wound repair. 金黄色葡萄球菌附属基因调节因子群体感应系统抑制角质细胞脂质酶和延迟伤口修复。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci190411

Michelle D Bagood,Jelena Marjanovic,Nina Jiang,Hung Chan,Tatsuya Dokoshi,Kellen J Cavagnero,Fengwu Li,Andrea Roso-Mares,Samia Almoughrabie,Edward Liu,Irena Pastar,Marjana Tomic-Canic,Alexander R Horswill,Richard L Gallo

{"title":"Staphylococcus aureus accessory gene regulator quorum-sensing system inhibits keratinocyte lipid enzymes and delays wound repair.","authors":"Michelle D Bagood,Jelena Marjanovic,Nina Jiang,Hung Chan,Tatsuya Dokoshi,Kellen J Cavagnero,Fengwu Li,Andrea Roso-Mares,Samia Almoughrabie,Edward Liu,Irena Pastar,Marjana Tomic-Canic,Alexander R Horswill,Richard L Gallo","doi":"10.1172/jci190411","DOIUrl":"https://doi.org/10.1172/jci190411","url":null,"abstract":"Mechanisms responsible for delayed wound repair are poorly understood despite the common impact of this disorder on health. To study how Staphylococcus aureus disrupts healing, mouse and human wound repair models were evaluated after exposure to S. aureus or commensal Staphylococcus. Quorum sensing by S. aureus, but not S. hominis, delayed repair and inhibited the expression of genes responsible for lipid metabolism in keratinocytes. S. aureus with inactive accessory gene regulator (agr) did not delay healing, and the inhibition of lipid metabolism was recapitulated in vitro by synthetic phenol soluble modulin α1 (psmα1) and psmα4, genes that are under agr control. However, S. aureus strains with single deletion of psmA, psmB, alpha-hemolysin (hla), or hld gene continued to delay repair, suggesting that S. aureus used multiple agr-dependent virulence factors to disrupt healing. These observations provide insight into mechanisms for delayed wound healing, identify quorum sensing as a critical event, and highlight the role of lipid biosynthesis in wound reepithelialization.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288468","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}

引用次数: 0

ANKRD55 is a key regulator of T cell inflammation in multiple sclerosis. ANKRD55是多发性硬化症中T细胞炎症的关键调节因子。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci195214

Chuyu Wu,Meiling Jiang,Xue Yang,Yixuan Liu,Bin Huang,Yi Guo,Runjing Cao,Zhihui Cui,Guozhen Deng,Weiyan Wang,Mengdi Guo,Zhiyong Lin,Jiahui Fan,Lin-Ming Zhang,Lorenzo Di Cesare Mannelli,Tao Pang,Chenhui Wang,Cun-Jin Zhang

{"title":"ANKRD55 is a key regulator of T cell inflammation in multiple sclerosis.","authors":"Chuyu Wu,Meiling Jiang,Xue Yang,Yixuan Liu,Bin Huang,Yi Guo,Runjing Cao,Zhihui Cui,Guozhen Deng,Weiyan Wang,Mengdi Guo,Zhiyong Lin,Jiahui Fan,Lin-Ming Zhang,Lorenzo Di Cesare Mannelli,Tao Pang,Chenhui Wang,Cun-Jin Zhang","doi":"10.1172/jci195214","DOIUrl":"https://doi.org/10.1172/jci195214","url":null,"abstract":"Multiple sclerosis (MS) is a progressive, chronic, and highly disabling neuroinflammatory disorder characterized by demyelination and T cell-driven inflammation. Pathogenic T cells play a central role in MS, but effective therapeutic targeting remains challenging. Here, we identified ankyrin repeat domain-containing protein 55 (ANKRD55) as a key regulator of T cell function by single-cell transcriptomic analysis of cerebrospinal fluid and blood from MS patients. ANKRD55 was predominantly expressed in CD4+ T cells in both compartments. Genetic ablation of Ankrd55 led to a robustly reduced disease severity and neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for MS. Furthermore, T cell-specific deficiency of Ankrd55 significantly impaired Th1 polarization and Th17 differentiation, reducing EAE pathogenicity. Mechanistically, we found that Ankrd55 deficiency disrupted T cell receptor (TCR) signaling integrity. We demonstrated that ANKRD55 regulates the formation of the immune synapse, an essential prerequisite for TCR activation, by interacting with subunits of the chaperonin-containing TCP1 (CCT) complex and modulating its activity, enhancing its assembly by competing with CCT5 for binding to TCP1, CCT3, and CCT6. This facilitates proper microtubule organization and TCR activation. These findings establish ANKRD55 as a critical regulator of TCR signaling and highlight its therapeutic potential in pathogenic T cell-driven autoimmune diseases.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288198","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}

引用次数: 0

Challenges of early detection of pancreatic cancer. 早期发现胰腺癌的挑战。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci191942

Michael J Shen,Arsia Jamali,Bryson W Katona

引用次数: 0

Stress, plasticity, and fibrosis: unfolding the role of the IRE1α/RIDD/Fgfr2 axis. 应激、可塑性和纤维化：揭示IRE1α/RIDD/Fgfr2轴的作用。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci196740

SeungHye Han

引用次数: 0

RCC2 and CD24 cooperate to modulate prostate cancer progression through vimentin ubiquitination and β-catenin activation. RCC2和CD24通过vimentin泛素化和β-连环蛋白激活共同调节前列腺癌的进展。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci192883

Xuelian Cui,Yicun Wang,Chao Zhang,Zhichao Liu,Haiyan Yu,Lizhong Wang,Jiangbing Zhou,Runhua Liu

{"title":"RCC2 and CD24 cooperate to modulate prostate cancer progression through vimentin ubiquitination and β-catenin activation.","authors":"Xuelian Cui,Yicun Wang,Chao Zhang,Zhichao Liu,Haiyan Yu,Lizhong Wang,Jiangbing Zhou,Runhua Liu","doi":"10.1172/jci192883","DOIUrl":"https://doi.org/10.1172/jci192883","url":null,"abstract":"CD24 promotes prostate cancer progression and metastasis by disrupting the ARF-NPM interaction and impairing p53 signaling. However, the mechanisms underlying CD24-driven metastasis remain unclear. This study identifies a novel interaction between CD24 and Regulator of Chromosome Condensation 2 (RCC2), a protein involved in cell proliferation and migration. IHC analysis of prostate adenocarcinoma samples showed frequent coexpression of CD24 (49%) and RCC2 (82%) with a positive correlation between coexpression of CD24 (49%) and RCC2 (82%). Functional assays revealed complex roles: RCC2 KO suppressed proliferation but increased migration and invasion, while CD24 KO reduced both proliferation and migration. Dual KO of CD24 and RCC2 further inhibited proliferation but had varied effects on migration. In mouse xenografts, RCC2 KO increased lung metastasis without significantly affecting primary tumor growth, while CD24 KO reduced both tumor growth and metastasis. Mechanistically, RCC2 controls migration by promoting ubiquitination and degradation of vimentin, affecting cytoskeletal dynamics. In contrast, CD24 targets RCC2 for degradation, thereby regulating β-catenin signaling. Notably, RCC2 KO enhances β-catenin activity by suppressing inhibitors AXIN2 and APC, whereas CD24 KO inhibits this pathway. These findings reveal a regulatory loop where CD24 and RCC2 reciprocally control proliferation and metastasis, positioning the CD24-RCC2 axis as a promising therapeutic target in prostate cancer.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288621","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}

引用次数: 0

Autoimmune neuropsychiatric disorders manifesting with psychosis. 以精神病为表现的自身免疫性神经精神障碍。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci196507

José Maria Cabrera-Maqueda,Jesús Planagumà,Mar Guasp,Josep Dalmau

{"title":"Autoimmune neuropsychiatric disorders manifesting with psychosis.","authors":"José Maria Cabrera-Maqueda,Jesús Planagumà,Mar Guasp,Josep Dalmau","doi":"10.1172/jci196507","DOIUrl":"https://doi.org/10.1172/jci196507","url":null,"abstract":"The increasing recognition of a new category of encephalitides that occur in association with antibodies against neuronal surface proteins has prompted the use of terms like \"autoimmune psychosis\" and \"autoimmune psychiatric disorders.\" However, although psychosis and other psychiatric symptoms can occur in autoimmune encephalitides and systemic autoimmune diseases, evidence for a distinct psychiatric entity beyond these conditions is lacking. A particularly defining condition is anti-NMDA receptor encephalitis, which has been central to promoting concepts such as autoimmune psychosis and autoimmune psychiatric disorders. While anti-NMDA receptor encephalitis can resemble primary psychiatric conditions, certain clinical features often suggest the specific diagnosis. This Review traces the development of the autoimmune psychosis concept and examines the implications of framing it as a separate entity. We discuss leading theories of psychosis and the convergence of the NMDA receptor hypofunction/glutamate hypothesis with anti-NMDA receptor encephalitis mechanisms. The interest generated by such disorders has driven uncontrolled antibody testing in psychiatric populations, often neglecting pretest probability and favoring prevalence over diagnostic specificity. Finally, we highlight the main limitations of current approaches and propose directions for future research.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288194","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}

引用次数: 0

Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice. ire1 α依赖性衰退的药理抑制可保护小鼠肺泡上皮的特性并防止肺纤维化。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci184522

Vincent C Auyeung,Tavienne L Steinberg,Alina Olivier,Luka Suzuki,Mary E Moreno,Imran S Khan,Michael S Downey,Maike Thamsen,Lu Guo,Dustin J Maly,Bradley J Backes,Dean Sheppard,Feroz R Papa

{"title":"Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.","authors":"Vincent C Auyeung,Tavienne L Steinberg,Alina Olivier,Luka Suzuki,Mary E Moreno,Imran S Khan,Michael S Downey,Maike Thamsen,Lu Guo,Dustin J Maly,Bradley J Backes,Dean Sheppard,Feroz R Papa","doi":"10.1172/jci184522","DOIUrl":"https://doi.org/10.1172/jci184522","url":null,"abstract":"Stress-induced epithelial plasticity is central to lung regeneration, fibrosis, and malignancy, but how cellular stress leads to differentiation is incompletely understood. Here, we found a central role for IRE1α, a conserved mediator of the unfolded protein response (UPR), in stimulating the plasticity of alveolar type 2 (AT2) cells. In single-cell RNA-seq, IRE1α activity was associated with loss of AT2 identity and progression toward a damage-associated transitional state unique to fibrosis. AT2 plasticity required destructive regulated IRE1α-dependent decay (RIDD), which we demonstrated by deploying PAIR2, a kinase modulator that inhibits RIDD while preserving IRE1α's adaptive XBP1 mRNA splicing activity. In vivo, selective inhibition of RIDD with PAIR2 reduced AT2 differentiation into profibrotic transitional cells and protected mice from bleomycin-induced pulmonary fibrosis. Mechanistically, we identified the Fgfr2 mRNA as a direct and regulated substrate for IRE1α's RNase in primary AT2 cells and in a biochemically reconstituted cell-free system. Loss of Fgf signaling caused AT2 differentiation, while gain of signaling protected cells from IRE1α-induced differentiation. We propose that IRE1α downregulates Fgf signaling through RIDD, provoking loss of AT2 identity and differentiation towards a profibrotic phenotype. Thus, IRE1α's RIDD activity emerges as a novel target for treatment of pulmonary fibrosis and potentially other diseases driven by aberrant epithelial cell plasticity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288619","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}

引用次数: 0

Cancer-associated fibroblasts enhance colorectal cancer lymphatic metastasis via CLEC11A/LGR5-mediated WNT pathway activation. 癌症相关成纤维细胞通过CLEC11A/ lgr5介导的WNT通路激活促进结直肠癌淋巴转移。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci194243

Chuhan Zhang,Teng Pan,Yuyuan Zhang,Yushuai Wu,Anning Zuo,Shutong Liu,Yuhao Ba,Benyu Liu,Shuaixi Yang,Yukang Chen,Hui Xu,Peng Luo,Quan Cheng,Siyuan Weng,Long Liu,Xing Zhou,Jingyuan Ning,Xinwei Han,Jinhai Deng,Zaoqu Liu

{"title":"Cancer-associated fibroblasts enhance colorectal cancer lymphatic metastasis via CLEC11A/LGR5-mediated WNT pathway activation.","authors":"Chuhan Zhang,Teng Pan,Yuyuan Zhang,Yushuai Wu,Anning Zuo,Shutong Liu,Yuhao Ba,Benyu Liu,Shuaixi Yang,Yukang Chen,Hui Xu,Peng Luo,Quan Cheng,Siyuan Weng,Long Liu,Xing Zhou,Jingyuan Ning,Xinwei Han,Jinhai Deng,Zaoqu Liu","doi":"10.1172/jci194243","DOIUrl":"https://doi.org/10.1172/jci194243","url":null,"abstract":"Hypoxia in the tumor microenvironment promotes lymphatic metastasis, yet the role of cancer-associated fibroblasts (CAFs) in this process remains insufficiently elucidated in colorectal cancer (CRC). In this study, we developed a large language model-based cellular hypoxia-predicting classifier to identify hypoxic CAFs (HCAFs) at single-cell resolution. Our findings revealed that HCAFs enhance CRC lymphatic metastasis by secreting CLEC11A, a protein that binds to the LGR5 receptor on tumor cells, subsequently activating the WNT/β-catenin signaling pathway. This promotes epithelial-mesenchymal transition and lymphangiogenesis, facilitating the spread of tumor cells via the lymphatic system. Furthermore, we demonstrate that the hypoxia-induced transcription factor HIF1A regulates the conversion of normoxic CAFs to HCAFs, driving CLEC11A expression and promoting metastasis. In vivo and vitro experiments confirmed the pro-metastatic role of CLEC11A in CRC, with its inhibition reducing lymphatic metastasis. This effect was markedly reversed by targeting the LGR5 receptor on tumor cells or inhibiting the WNT/β-catenin pathway, further elucidating the underlying mechanisms of CLEC11A-driven metastasis. These findings underscore the potential of targeting the CLEC11A-LGR5 axis to prevent lymphatic dissemination in CRC. Our study highlights the role of HCAFs in CRC progression and reveals mechanisms of lymphatic metastasis for intervention.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288196","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}

引用次数: 0

C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling. C6orf223通过促进PRMT5-MEP50多蛋白复合物的组装促进结直肠癌的生长和转移。

The Journal of Clinical Investigation Pub Date : 2025-10-15 DOI: 10.1172/jci186052

Yufeng Qiao,Zhenzhen Wu,Peng Wang,Yiliang Jin,Furong Bai,Fei Zhang,Yunhe An,Meiying Xue,Han Feng,Yong Zhang,Yaxin Hou,Junfeng Du,Huiyun Cai,Guizhi Shi,Bing Zhou,Pu Gao,Jizhong Lou,Peng Zhang,Kelong Fan,Jinbo Liu,Pengcheng Bu

{"title":"C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling.","authors":"Yufeng Qiao,Zhenzhen Wu,Peng Wang,Yiliang Jin,Furong Bai,Fei Zhang,Yunhe An,Meiying Xue,Han Feng,Yong Zhang,Yaxin Hou,Junfeng Du,Huiyun Cai,Guizhi Shi,Bing Zhou,Pu Gao,Jizhong Lou,Peng Zhang,Kelong Fan,Jinbo Liu,Pengcheng Bu","doi":"10.1172/jci186052","DOIUrl":"https://doi.org/10.1172/jci186052","url":null,"abstract":"Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288618","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}

引用次数: 0