{"title":"Targeting oncogenic SOX2 condensates suppresses squamous cell carcinoma progression.","authors":"Siyuan Luan, Jun Sun, Yijun Dong, Jin Tan, Xin Xiao, Jintong Zhang, Xiaokun Li, Jianfeng Zhou, Pinhao Fang, Haowen Zhang, Shangwei Sun, Zewen Wang, Jian Wang, Tara Sr Chen, Xiaoting Chen, Yushang Yang, Haopeng Yu, Hui Yang, Longqi Chen, Xiaoxi Zeng, An-Yuan Guo, Junjun Ding, Yong Yuan","doi":"10.1016/j.xcrm.2026.103117","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103117","url":null,"abstract":"<p><p>Squamous cell carcinomas (SCCs) comprise a group of lethal malignancies, yet developing SCC-specific therapies remains challenging, largely due to a lack of druggable targets. We identify SOX2 condensation as a shared cancer hallmark across esophageal, head and neck, and lung SCCs. Within SOX2, the activation domain 1 (AD1) acts as the condensate-promoting region via its aromatic and hydrophobic residues. Site-specific mutagenesis, orthotopic mouse models, and multi-omics sequencing demonstrate that SOX2 condensates upregulate oncogene expression by enhancing SOX2 chromatin occupancy, H3K27ac enrichment, and chromatin interactions at oncogenic loci such as FGFR2, thereby promoting SCC progression. An FDA-approved drug screen reveals that the proteasome inhibitor ixazomib disrupts SOX2 condensates in an HSP70-dependent manner. Upon ixazomib treatment, the substrate-binding domain of HSP70 blocks SOX2 AD1, selectively dissolving SOX2 condensates, downregulating oncogene expression, and suppressing condensate-positive SCC patient-derived xenografts. These findings highlight targeting SOX2 condensates with proteasome inhibitors as an SCC-specific, biomarker-guided therapeutic strategy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103117"},"PeriodicalIF":14.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223441","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":"Isobavachalcone targets deubiquitinase OTUB1 to induce PD-L1 degradation and enhances antitumor immunity.","authors":"Qing Zhang, Simeng Li, Mengting Xu, Hanchi Xu, Haiyang Zhou, Hongmei Hu, Dianping Yu, Linyang Li, Xiaoyu Tao, Xuwen Lin, Xinru Li, Shize Xie, Xinying Xue, Qun Wang, Tao Yang, Weidong Zhang, Sanhong Liu","doi":"10.1016/j.xcrm.2026.103113","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103113","url":null,"abstract":"<p><p>PD-L1-mediated immunosuppression is a key mechanism underlying tumor immune evasion, whereas PD-1/PD-L1 blockade therapies remain limited by low response rates and acquired resistance. Through small-molecule screening, we identify isobavachalcone (IBC), a naturally derived compound that modulates PD-L1 homeostasis by targeting the deubiquitinase OTUB1. Mechanistically, IBC targets OTUB1 at the His217 residue and suppresses its deubiquitinase activity, thereby promoting K48-linked polyubiquitination of PD-L1 and its proteasome-dependent degradation. Functionally, IBC reduces tumor cell PD-L1 expression and enhances CD8<sup>+</sup> T cell-mediated cytotoxicity. In PD-L1-deficient tumor models, IBC fails to further enhance antitumor activity, indicating that PD-L1 is required for IBC-mediated immune regulation. Moreover, IBC combined with anti-CTLA-4 therapy further enhanced antitumor efficacy. Together, these findings highlight IBC as a potential drug candidate that promotes PD-L1 degradation and demonstrate the therapeutic potential of targeting the OTUB1-PD-L1 axis to improve immune checkpoint therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103113"},"PeriodicalIF":14.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223366","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":"Targeting MMGT1 enhances immunotherapy efficacy in triple-negative breast cancer.","authors":"Shaoqing Liu, Hongbing Liu, Mengying Zhang, Kaiyuan Guo, Shilin Tong, Nuo Jiang, Jinxue Zhou, Linlin Yan, Mien-Chie Hung, Chenhao Zhou, Yanzhao Zhou, Min Xu","doi":"10.1016/j.xcrm.2026.103120","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103120","url":null,"abstract":"<p><p>The role of senescent tumor cells in modulating the immune microenvironment and influencing immunotherapy efficacy remains poorly understood. In this study, we investigate the function of the senescence-associated gene membrane magnesium transporter 1 (MMGT1) in triple-negative breast cancer (TNBC) immunotherapy. MMGT1 is upregulated in TNBC and correlates with poor prognosis. Mammary gland-specific knockout of Mmgt1 significantly impedes tumor growth. Mechanistically, MMGT1 promotes lipid metabolism by facilitating translocation of the SCAP-SREBP1 complex to the Golgi apparatus, thereby suppressing cellular senescence. Notably, senescent TNBC cells enhance CD8<sup>+</sup> T cell proliferation and cytotoxicity through CCL20 secretion. Furthermore, a positive feedback loop exists between MMGT1 and SREBP1. In vivo, AZ191 downregulates MMGT1 expression, which suppresses tumor growth and enhances the efficacy of anti-PD-1 therapy. Collectively, these findings reveal a critical role for MMGT1 in shaping the TNBC immune microenvironment and suggest that targeting MMGT1 represents a promising strategy to improve anti-PD-1 immunotherapy outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103120"},"PeriodicalIF":14.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206593","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}
Jiajia Li, Lu Han, Qi Zhu, Nan Liu, Hongyu Ma, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han
{"title":"NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands.","authors":"Jiajia Li, Lu Han, Qi Zhu, Nan Liu, Hongyu Ma, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han","doi":"10.1016/j.xcrm.2026.103116","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103116","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, but durable efficacy remains limited by insufficient CAR-T cell persistence. Here, we show that activated CAR-T cells upregulate multiple NKG2D ligands (NKG2DLs), increasing their susceptibility to natural killer (NK) cell-mediated CAR-T cell cytotoxicity. To address this vulnerability, we engineer CAR-T cells to overexpress full-length NKG2D (CAR-NG). NKG2D overexpression reduces the surface accessibility of endogenous NKG2DLs without decreasing their total protein abundance. In parallel, engagement of tumor-expressed NKG2DLs in trans provides additional costimulatory signals, enhancing CAR-T cell activation and proliferation while attenuating exhaustion-associated phenotypes. In hematologic and solid tumor models, CAR-NG cells exhibit reduced susceptibility to NK-cell-mediated cytotoxicity, improved tumor control, increased in vivo expansion, deeper tumor infiltration, and no evident additional toxicity compared with conventional CAR-T cells. These findings identify NKG2D overexpression as an engineering strategy that enhances CAR-T antitumor activity primarily through tumor NKG2DL-dependent trans costimulation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103116"},"PeriodicalIF":14.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206527","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":"Safety and efficacy of high-current tTIS targeting left sgACC for major depressive disorder: A randomized, double-blind, sham-controlled trial.","authors":"Mengmeng Wang, Wei Wu, Quanming Zheng, Hao Zhou, Jiecheng Ren, Huixing Gou, Xue'er Meng, Guanbao Cui, Jingjing Sun, Jiahui Zhou, Xiyun Chen, Jian Guo, Shikang Li, Zhen He, Dexue Ge, Gang Wang, Qiuyu Yuan, Dongliang Jiao, Xinming Yu, Bin Wang, Mingsong Zhang, Chuangchuang Chang, Ginger Qinghong Zeng, Xiaochu Zhang","doi":"10.1016/j.xcrm.2026.103112","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103112","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a leading cause of disability, and non-invasive stimulation of deep brain circuits such as the subgenual anterior cingulate cortex (sgACC) remains challenging. This randomized, double-blind, sham-controlled trial recruits 96 adults with moderate-to-severe MDD who received 10 sessions of 2 mA low-current, 15 mA high-current, or sham transcranial temporal interference stimulation (tTIS) targeting the left sgACC. The high-current group shows significantly greater reductions in depressive symptoms (17-item Hamilton Depression Rating Scale [HDRS-17] score) post-treatment and at 1-month follow-up compared with sham and outperforms the low-current group post-treatment. Exploratory Pittsburgh Sleep Quality Index (PSQI) analyses suggest improved sleep quality in both active groups, whereas anxiety outcomes show no intergroup differences. High-current tTIS is safe and well tolerated, with only transient tingling. These findings provide preliminary evidence that sgACC-targeted tTIS relieves depressive symptoms safely, with more robust short-to medium-term effects observed under the 15 mA protocol. This trial registers on Chictr.org.cn (ChiCTR2400094971).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103112"},"PeriodicalIF":14.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191693","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}
David Braun, Nicholas Dana, Hilary R Hernan, Shalini Sahni, Christina M Scribano, Christin Johnson, Lindsey Vedder, Erika von Euw, Julie Zweng, Ellen Wargowski, Aishwarya Sunil, Deepa Sharma, Josh Routh, Katherine Rexroad, Amreen Nasreen, Payton McDonnell, Victor Jergens, Catarina Costa, Richard Zuniga, Giuseppe V Toia, Paras M Patel, Stephanie McGregor, Robert C G Martin, Umair Majeed, Debabrata Mukhopadhyay, Yanyan Lou, Nima Kokabi, James W Jakub, David Hays, Andrew K Godwin, Victoria Giffi, Alexander Gelbard, Andreas Friedl, Emma Kate Duimstra, Roxana S Dronca, Ruqin Chen, Heather Chalfin, Santanu Bhattacharya, Barbara Broome, Hani M Babiker, Tarun Chandra, Sean Caenepeel, Laura C F Hrycyniak, Chetan Sood, Hilario Ramos, Premal Patel, Pooja Advani, Hinco J Gierman, Janis Taube
{"title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies.","authors":"David Braun, Nicholas Dana, Hilary R Hernan, Shalini Sahni, Christina M Scribano, Christin Johnson, Lindsey Vedder, Erika von Euw, Julie Zweng, Ellen Wargowski, Aishwarya Sunil, Deepa Sharma, Josh Routh, Katherine Rexroad, Amreen Nasreen, Payton McDonnell, Victor Jergens, Catarina Costa, Richard Zuniga, Giuseppe V Toia, Paras M Patel, Stephanie McGregor, Robert C G Martin, Umair Majeed, Debabrata Mukhopadhyay, Yanyan Lou, Nima Kokabi, James W Jakub, David Hays, Andrew K Godwin, Victoria Giffi, Alexander Gelbard, Andreas Friedl, Emma Kate Duimstra, Roxana S Dronca, Ruqin Chen, Heather Chalfin, Santanu Bhattacharya, Barbara Broome, Hani M Babiker, Tarun Chandra, Sean Caenepeel, Laura C F Hrycyniak, Chetan Sood, Hilario Ramos, Premal Patel, Pooja Advani, Hinco J Gierman, Janis Taube","doi":"10.1016/j.xcrm.2026.103114","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103114","url":null,"abstract":"<p><p>Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy across prospective, multicenter observational studies. Hierarchical clustering of changes in cytokine production between an IgG baseline phase and an ICI treatment phase identified two clusters: heatmap responder and nonresponder. A binary classifier (elive index) using eight cytokines achieved an area under the curve (AUC) of 0.99 for heatmap cluster prediction. elive index aligned with clinical benefit in 93% (26/28) of patients (p = 3.2 × 10<sup>-5</sup>) and identified 83% (10/12) of objective responders. elive responders were found among biomarker-negative patients, highlighting the platform as a scalable approach that may complement existing companion diagnostics. This study was registered at ClinicalTrials.gov (NCT05478538, NCT05520099, NCT06349642, and NCT07327489).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103114"},"PeriodicalIF":14.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191730","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}
Lexuan Wang, Yang Chen, Yanyu Shang, Jia Liu, Muyuan Zhao, Lei Jin, Yichenxi Shi, Ruili Zhang, Zhuang Chen, Ting Yin, Chaoqiang Qiao, Zhongliang Wang
{"title":"Orally delivered metabolically reprogrammed probiotics for cascade-activated antitumor immunity in colorectal cancer.","authors":"Lexuan Wang, Yang Chen, Yanyu Shang, Jia Liu, Muyuan Zhao, Lei Jin, Yichenxi Shi, Ruili Zhang, Zhuang Chen, Ting Yin, Chaoqiang Qiao, Zhongliang Wang","doi":"10.1016/j.xcrm.2026.103111","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103111","url":null,"abstract":"<p><p>Immunotherapy for colorectal cancer (CRC) remains limited due to the inherently low tumor immunogenicity and the profoundly immunosuppressive tumor microenvironment (TME). Herein, capitalizing on the metabolic traits and anatomical accessibility of CRC, we propose a broadly applicable oral strategy based on metabolically engineered bacteria (EcN-HlpA-CGL [EHC]) for CRC immunotherapy. Mechanistically, cystathionine γ-lyase expressed by EHC disrupts redox homeostasis, triggering ferroptosis in CRC cells and thereby enhancing tumor immunogenicity. Concurrently, the intrinsic adjuvant activity of the bacteria amplifies the cancer-immunity cycle driven by immunogenic cell death and remodels the immunosuppressive TME. In vivo studies demonstrate that this orally delivered engineered bacterial platform not only suppresses the growth of orthotopic CRC tumors but also inhibits metastatic progression, indicating the induction of a potent systemic immune response. Immune profiling confirms robust systemic and gut mucosal immune activation following oral administration. Collectively, this oral metabolically engineered bacterial platform is precisely tailored to the features of CRC and offers a safe and effective immunotherapeutic strategy for this malignancy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103111"},"PeriodicalIF":14.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167239","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}
Elena Cabello-Yeves, Anna Samarra, Kimberley Summers, Iñaki Comas, Elizabeth Wellington, Andrew Millard, María Carmen Collado, Alberto Marina
{"title":"Breastfeeding and maternal microbial reservoirs are associated with infant gut phageome development during the first year of life.","authors":"Elena Cabello-Yeves, Anna Samarra, Kimberley Summers, Iñaki Comas, Elizabeth Wellington, Andrew Millard, María Carmen Collado, Alberto Marina","doi":"10.1016/j.xcrm.2026.103107","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103107","url":null,"abstract":"<p><p>The early-life assembly of the gut microbiome is a critical determinant of long-term health, yet the role of bacteriophages in this process remains poorly understood. Here we longitudinally profile the gut phageome of 34 mother-infant dyads during the first year of life with metagenomics and a phage-centered computational workflow. Phage diversity increases with age, paralleling bacterial diversification but following distinct ecological trajectories. Shared viral populations across maternal and infant samples are consistent with potential maternal contribution, although not indicative of direct transmission. Feeding-related variables are consistently associated with phageome composition at specific developmental stages. No single factor fully explains phageome variation, supporting a multifactorial model involving maternal, environmental, and dietary inputs. Together, these findings provide a framework for understanding early-life phage ecology, positioning phages as active participants in early microbiome assembly and supporting the inclusion of viral components in microbiome-based strategies aimed at promoting healthy ecosystem development in infancy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103107"},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147474","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}
William S O Symmans, Ziyi Li, George A Calin, Akanksha Samuel
{"title":"AI-integrated RNA therapeutics in precision oncology.","authors":"William S O Symmans, Ziyi Li, George A Calin, Akanksha Samuel","doi":"10.1016/j.xcrm.2026.103100","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103100","url":null,"abstract":"<p><p>RNA therapeutics can silence oncogenic transcripts, modulate RNA processing, restore protein expression, or encode tumor antigens. Their development, however, is constrained by target selection, molecular design, delivery, immunogenicity, and inter-patient heterogeneity. Artificial intelligence (AI) is increasingly applied to these bottlenecks through multi-omics target prioritization, RNA structure and sequence modeling, delivery optimization, neoantigen selection, patient stratification, and manufacturing quality control. The maturity of these applications is uneven: within oncology, messenger RNA (mRNA) cancer vaccines are the most clinically advanced RNA-based strategy, whereas therapeutic approaches involving long non-coding RNAs and circular RNAs remain predominantly preclinical or early clinical, and most AI-enabled methods lack prospective clinical validation. In this review, we evaluate AI across the RNA therapeutic development pipeline, distinguish evidence-supported applications from preclinical and speculative uses, and discuss the validation, regulatory, and data-governance requirements for translation into precision oncology.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103100"},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147556","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":"Microbiota-regulated TCDCA associates with Parkinson's disease severity and promotes BBB dysfunction through VSMC TGR5 signaling in mice.","authors":"Zhe Zhao, Yixuan Liu, Wen Ma, Gaofei Hu, Jincen Hao, Chaobo Bai, Jing Chen, Qi Zhang, Huanhuan Cao, Xiaoyi Liu, Yujie Zhu, Manyuan Dong, Zheng Zhang, Shenge Su, Rui Zhan, Huibo Li, Rongsheng Zhao, Junliang Yuan","doi":"10.1016/j.xcrm.2026.103098","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103098","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a systemic disorder linked to gut dysbiosis, yet key microbiota-regulated metabolites remain unclear. Here, we observe elevated taurochenodeoxycholic acid (TCDCA) in patients with PD that correlates with disease severity. Reduced bile salt hydrolase (BSH) gene abundance correlates inversely with circulating TCDCA, consistent with altered bile acid deconjugation. Exogenous TCDCA correlates with aggravated motor and gastrointestinal deficits, impaired blood-brain barrier (BBB) integrity, and accelerated dopaminergic neurodegeneration in a PD mouse model. Mechanistically, TCDCA links to TGR5 signaling activation in vascular smooth muscle cells (VSMCs), alongside PKCα-dependent mitochondrial apoptosis and BBB disruption. VSMC-specific Tgr5 deletion coincides with neurovascular protection. Supplementation with a BSH-high Lactobacillus reuteri strain reduces TCDCA concentrations, improves gut and BBB integrity, mitigates inflammation, and alleviates PD-like phenotypes in a BSH-dependent manner. These data support a gut-BBB-brain axis linked to PD, identifying TCDCA as a candidate pathological marker.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103098"},"PeriodicalIF":14.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148482","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}
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