Deqian Chen, Yong Zhan, Enqing Zhou, Huifen Chen, Shuyang Dai, Ran Yang, Chunjing Ye, Junfeng Wang, Yi Li, Yifei Lu, Ying Fang, Lian Chen, Wei Yao, Kai Li, Shan Zheng, Kuiran Dong, Jia Wang, Rui Dong
{"title":"Single-cell profiles delineate immune cell remodeling and enhanced tumor-fibroblast interaction of hepatoblastoma after chemotherapy.","authors":"Deqian Chen, Yong Zhan, Enqing Zhou, Huifen Chen, Shuyang Dai, Ran Yang, Chunjing Ye, Junfeng Wang, Yi Li, Yifei Lu, Ying Fang, Lian Chen, Wei Yao, Kai Li, Shan Zheng, Kuiran Dong, Jia Wang, Rui Dong","doi":"10.1016/j.xcrm.2025.102401","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102401","url":null,"abstract":"<p><p>Hepatoblastoma (HB), the most common pediatric liver cancer, is typically treated with chemotherapy, yet its impact on the tumor microenvironment (TME) and mechanisms of chemoresistance remain unclear. We perform single-cell RNA sequencing (scRNA-seq) on 32 HB tumors pre- and post-chemotherapy, integrating data from spatial transcriptomics, bulk transcriptomics, multiplexed immunofluorescence, and patient-derived xenografts. Chemotherapy enriches CD69<sup>+</sup>CD8<sup>+</sup> T cells and shifted myeloid cells toward immune-activating phenotypes. HB tumor cells exhibit both hepatic and mesenchymal features, with hepatic-like cells showing greater chemoresistance. A subset of AFP-high hepatic tumor cells expresses high fibroblast growth factor receptor 4 (FGFR4) and showed elevated proliferation. Post-treatment, mesenchymal-like tumor cells and MMP11<sup>+</sup> cancer-associated fibroblasts enhance FGF-FGFR signaling. FGFR4 inhibition significantly suppressed tumor growth in xenografts. These findings provide a high-resolution landscape of the HB immune TME and highlight cancer-fibroblast interactions, especially via FGF signaling, as key contributors to chemoresistance.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102401"},"PeriodicalIF":10.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211805","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":"Designer probiotic-based living drugs for uric acid homeostasis control in hyperuricemic mice and rats.","authors":"Xianyun Gao, Yiyu Jin, Mengyao Liu, Wenbo Ma, Deqiang Kong, Yang Zhou, Lingxue Niu, Jianli Yin, Haibing Chen, Haifeng Ye, Ningzi Guan","doi":"10.1016/j.xcrm.2025.102379","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102379","url":null,"abstract":"<p><p>Engineered probiotics can effectively manage hyperuricemia, a condition characterized by increased serum uric acid (UA) levels, leading to several chronic diseases. In this study, we design a probiotic-based UA level sensing and adjustment (PULSE)-engineered bacterium to maintain UA homeostasis. We generate a UA sensor in the E. coli Nissle 1917 strain based on a UA-responsive transcriptional repressor HucR, integrated with a synthetic promoter. Upon oral administration of engineered probiotics, PULSE cells dynamically regulate urate oxidase expression, reducing UA in the gastrointestinal tract in response to increased serum levels. We have demonstrated the potential of PULSE-engineered bacteria in maintaining UA balance in acute and chronic hyperuricemic mouse and rat models, highlighting the potential for long-term oral administration in reducing hyperuricemia-associated renal damage. Our probiotic-based living drug supports the progress of engineered probiotics as a safe, effective, and patient-friendly alternative to typical therapeutics for chronic disease management.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102379"},"PeriodicalIF":10.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211798","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":"A sequential dual-site repetitive transcranial magnetic stimulation for major depressive disorder: A randomized clinical trial.","authors":"Yi-Jie Zhao, Shitong Xiang, Ruiqin Chen, Qiong Ding, Ruijie Geng, Yuan Wang, Yuanyuan Li, Haibin Li, Yichen Wang, Hailun Cui, Ying Huang, Jianfeng Feng, Wenjuan Liu, Valerie Voon","doi":"10.1016/j.xcrm.2025.102402","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102402","url":null,"abstract":"<p><p>Repetitive transcranial magnetic stimulation (rTMS) is approved for major depressive disorder (MDD), but it is limited by variable efficacy. Here, we examine antidepressant effects of our sequential dorsolateral prefrontal cortex (dlPFC)-dorsomedial prefrontal cortex (dmPFC) accelerated rTMS protocol, which includes a 4-day treatment with 4 sessions per day. At week 4, the Montgomery-Åsberg Depression Rating Scale (MADRS) reduction is significantly larger in the active group, and critical, significant differences were apparent on day 4. For active and sham-controlled groups, respectively, response rates are 57.69% and 23.08%, and remission rates are 38.46% and 15.38%. Of responders, over 85% remain in remission over 6 months. Resting-state fMRI shows dissociable symptom improvement associated with increased dlPFC-frontoparietal and decreased dmPFC-amygdalo-subcallosal cingulate functional connectivity. We highlight a cost-efficient generalizable rTMS approach targeting differential networks in MDD, which shows rapid and sustained antidepressant effects with a relatively small number of pulses and minimal treatment duration. The study is registered with ChiCTR (ChiCTR2100046042).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102402"},"PeriodicalIF":10.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211790","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}
Alex Quan, Mingyu Huo, Dan Li, Laura E Hutchins, Constanza Rodriguez, Jangsuk Oh, Hsi-En Tsao, Madeline Spetz, Elijah Edmondson, Dana Ashworth, Rui Zheng, Jing Zhou, Jinyun Chen, Jingbao Liu, Guangyan Xiong, Hongbing Zhang, Cheng Liu, Rosa Nguyen, Nan Li, Mitchell Ho
{"title":"Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density.","authors":"Alex Quan, Mingyu Huo, Dan Li, Laura E Hutchins, Constanza Rodriguez, Jangsuk Oh, Hsi-En Tsao, Madeline Spetz, Elijah Edmondson, Dana Ashworth, Rui Zheng, Jing Zhou, Jinyun Chen, Jingbao Liu, Guangyan Xiong, Hongbing Zhang, Cheng Liu, Rosa Nguyen, Nan Li, Mitchell Ho","doi":"10.1016/j.xcrm.2025.102378","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102378","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells have shown promise in hematological cancers but face challenges in solid tumors, partly due to heterogeneous antigen density. Glypican-2 (GPC2) is an oncofetal antigen highly expressed in neuroblastoma and under evaluation in phase 1 clinical trials. Here, we engineer T cells with antibody-T cell receptors (AbTCRs) targeting GPC2. We generate autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to γ/δ T cell receptors (TCRs), along with a CD30 co-stimulatory domain. Both CT3 and hCT3 AbTCR T cells show superior antitumor efficacy compared to CT3 CAR T cells, with hCT3 AbTCR T cells inducing significant regression in neuroblastoma with low GPC2 antigen density. Enhanced efficacy is associated with stronger TCR signaling, expansion of stem cell-like memory T cells, and improved CD8<sup>+</sup> T cell infiltration. These results highlight the potential of hCT3 AbTCR T cells for neuroblastoma and indicate broad application of AbTCR T cells in solid tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102378"},"PeriodicalIF":10.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198498","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}
Ryan James Rebernick, Jae Eun Choi, Calvin Hesse, Noshad Hosseini, Alec Chu, Jin Zhou, Yu Ning, Rui Wang, Xuhong Cao, Meredith Irwin, Yi-Mi Wu, Chandan Kumar, Raja Rabah, Rochelle Bagatell, Arul M Chinnaiyan, Rajen Mody, Marcin Cieslik
{"title":"Chromosomal instability degrades developmental phenotypes essential for anti-GD2 immunotherapy outcomes in high-risk neuroblastoma.","authors":"Ryan James Rebernick, Jae Eun Choi, Calvin Hesse, Noshad Hosseini, Alec Chu, Jin Zhou, Yu Ning, Rui Wang, Xuhong Cao, Meredith Irwin, Yi-Mi Wu, Chandan Kumar, Raja Rabah, Rochelle Bagatell, Arul M Chinnaiyan, Rajen Mody, Marcin Cieslik","doi":"10.1016/j.xcrm.2025.102375","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102375","url":null,"abstract":"<p><p>High-risk neuroblastoma (HR-NBL) is a pediatric malignancy that arises during sympathoadrenal development and expresses the surface disialoganglioside GD2. Monoclonal anti-GD2 immunotherapy is a mainstay of HR-NBL treatment; however, it is associated with severe toxicities. Genomic correlates of outcomes following multimodality therapy containing anti-GD2 immunotherapy are limited. We profile 840 tumors and identify actionable ALK gene fusions in HR-NBL. We leverage fetal sympathoadrenal single-cell RNA sequencing to characterize patients with improved post-multimodality outcomes. We demonstrate that patients with improved outcomes have tumors that upregulate noradrenergic and metabolic phenotypes characteristic of mature sympathoblasts-a fetal sympathoadrenal cell population. We show that loss of these developmental phenotypes is mediated by chromosome 11q loss. Targeted analysis of 19 biopsy pairs identifies significant clonal evolution and accumulation of cell-cycle mutations following multimodality treatment. Collectively, we identify chromosomal instability-specifically 11q loss-as key in degrading developmental phenotypes critical for outcomes following multimodality therapy containing anti-GD2 immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102375"},"PeriodicalIF":10.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181941","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}
Fei Liu, Yue Niu, Qihua Zhang, Kai Wang, Zheyi Dong, Io Nam Wong, Linling Cheng, Ting Li, Lian Duan, Kun Li, Gen Li, Tai Wa Hou, Manson Fok, Huiyan Luo, Xiangmei Chen, Kang Zhang, Yun Yin
{"title":"A foundational architecture for AI agents in healthcare.","authors":"Fei Liu, Yue Niu, Qihua Zhang, Kai Wang, Zheyi Dong, Io Nam Wong, Linling Cheng, Ting Li, Lian Duan, Kun Li, Gen Li, Tai Wa Hou, Manson Fok, Huiyan Luo, Xiangmei Chen, Kang Zhang, Yun Yin","doi":"10.1016/j.xcrm.2025.102374","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102374","url":null,"abstract":"<p><p>Medical AI agents represent a transformative paradigm in healthcare, distinguished from traditional AI by their autonomy, adaptability, and ability to manage complex tasks. This review introduces a conceptual framework for these agents built on four core components: planning, action, reflection, and memory. We examine the framework's application across key clinical domains, from enhancing diagnostic accuracy and personalizing treatment to guiding robotic surgery and enabling real-time patient monitoring. The review critically analyzes implementation challenges, including technical integration, clinician adoption, regulatory adaptation, and ethical considerations like data privacy and algorithmic bias. Future directions are explored, including the shift toward proactive, multi-agent collaborative systems and the visionary AI Agent Hospital concept. While these agents hold immense potential to revolutionize healthcare delivery by improving efficiency and patient outcomes, their successful and equitable integration hinges on navigating these profound technical, ethical, and regulatory hurdles.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102374"},"PeriodicalIF":10.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181967","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}
Letizia Fontana, Pierre Martinucci, Simone Amistadi, Tristan Felix, Margaux Mombled, Alexandra Tachtsidi, Guillaume Corre, Anne Chalumeau, Giulia Hardouin, Jeanne Martin, Oriana Romano, Mario Amendola, Panagiotis Antoniou, Annarita Miccio
{"title":"Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.","authors":"Letizia Fontana, Pierre Martinucci, Simone Amistadi, Tristan Felix, Margaux Mombled, Alexandra Tachtsidi, Guillaume Corre, Anne Chalumeau, Giulia Hardouin, Jeanne Martin, Oriana Romano, Mario Amendola, Panagiotis Antoniou, Annarita Miccio","doi":"10.1016/j.xcrm.2025.102376","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102376","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is a genetic anemia caused by the production of an abnormal adult hemoglobin. Elevated levels of fetal hemoglobin (HbF) in adulthood reduce disease severity. A promising therapy involves the treatment of hematopoietic stem/progenitor cells (HSPCs) with CRISPR-Cas9 to downregulate the HbF repressor BCL11A via generation of double-strand breaks (DSBs) in the +58-kb enhancer. To improve safety and HbF induction, we use base editors to target both the +58-kb and +55-kb enhancers without generating DSBs. We dissect key DNA motifs recognized by transcriptional activators and identify critical nucleotides. Multiplex base editing efficiently disrupts these sites, reactivating HbF to levels exceeding those achieved with CRISPR-Cas9-induced editing, while minimizing DSBs and genomic rearrangements. Base editing is effective in long-term repopulating HSPCs and results in robust HbF reactivation in vivo. These findings demonstrate that multiplex base editing of BCL11A enhancers is a safe, efficient, and durable strategy to treat SCD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102376"},"PeriodicalIF":10.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181909","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}
Ming Xie, Jun Zheng, Yao Yu, Qishen Yang, Zhipeng Zhou, Jingwen Xue, Benlin Wang, Yifeng Qiu, Zhangrui Zhu, Qi Sun, Xinhang Shi, Wentai Shangguan, Leqian Li, Zhipeng Zou, Jie Zhao, Peng Wu
{"title":"Gut symbiont-derived ursodeoxycholic acid promotes fatty acid oxidation to protect against renal ischemia-reperfusion injury.","authors":"Ming Xie, Jun Zheng, Yao Yu, Qishen Yang, Zhipeng Zhou, Jingwen Xue, Benlin Wang, Yifeng Qiu, Zhangrui Zhu, Qi Sun, Xinhang Shi, Wentai Shangguan, Leqian Li, Zhipeng Zou, Jie Zhao, Peng Wu","doi":"10.1016/j.xcrm.2025.102373","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102373","url":null,"abstract":"<p><p>Renal ischemia-reperfusion injury (IRI) is a common complication of renal surgery that currently lacks effective prevention or treatment strategies. The gut microbiota and their metabolites are closely associated with kidney injury. However, the exact mechanisms underlying this link are unclear. Here, we find that renal IRI reduces ursodeoxycholic acid (UDCA), a metabolite of Eubacterium limosum (E. limosum), in mice cecal content and serum. Conversely, supplementation with either E. limosum or UDCA prevents these mice from IRI. Mechanistically, UDCA directly binds and activates peroxisome proliferator-activated receptor-gamma (PPARγ) to increase fatty acid oxidation, inducing ATP production and reducing lipid accumulation in proximal tubular epithelial cells, ultimately protecting the kidney against IRI. Importantly, while renal IRI in patients markedly lowers their serum UDCA, patients with higher pre-IRI UDCA or E. limosum level develop less severe IRI. Collectively, our findings highlight the rationale of using UDCA and E. limosum for the prevention or treatment of renal IRI.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102373"},"PeriodicalIF":10.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181931","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}
Qian Zhou, Yuming Sun, Songtao Du, Yating Dian, Lei Yao, Hui Su, Ziyu Guo, Yu Meng, Yixiao Xiong, Zhili Deng, Xinwei Kuang, Xiaowei Liang, Hong Liu, Guangtong Deng, Xiang Chen, Furong Zeng
{"title":"Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis.","authors":"Qian Zhou, Yuming Sun, Songtao Du, Yating Dian, Lei Yao, Hui Su, Ziyu Guo, Yu Meng, Yixiao Xiong, Zhili Deng, Xinwei Kuang, Xiaowei Liang, Hong Liu, Guangtong Deng, Xiang Chen, Furong Zeng","doi":"10.1016/j.xcrm.2025.102371","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102371","url":null,"abstract":"<p><p>Immunotherapy has revolutionized cancer treatment, yet challenges persist, such as resistance and lethal thromboembolism, necessitating dual-purpose strategies. Targeting ferroptosis emerges as a promising strategy to enhance immunotherapy efficacy, prompting our investigation of antiplatelet agents that simultaneously promote ferroptosis and mitigate thromboembolic risks. Through systematic screening of 20 Food and Drug Administration (FDA)-approved antiplatelet agents, we identify vorapaxar as a potent pro-ferroptotic drug. Mechanistically, vorapaxar binds forkhead box O1 (FOXO1), inhibits its phosphorylation at Ser256, and facilitates nuclear translocation to upregulate heme oxygenase 1 (HMOX1), promoting mitochondrial iron overload and mitochondria-associated ferroptosis. Vorapaxar enhances immunotherapy-induced tumor ferroptosis and antitumor immunity across diverse melanoma models, including B16F10 tumor-bearing mice, Braf/Pten-driven spontaneous melanoma mice, and peripheral blood mononuclear cell (PBMC)-humanized mice. Clinically, high FOXO1/HMOX1 co-expression correlates with improved immunotherapy response and progression-free survival. These findings position vorapaxar as a promising adjunct to immunotherapy, offering a dual benefit for cancer patients requiring both antithrombotic therapy and immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102371"},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173957","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":"Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity.","authors":"Xiaojing Jia, Hong Lin, Yilan Ding, Chunyan Hu, Shuangyuan Wang, Mian Li, Yu Xu, Min Xu, Feiyue Huang, Feixia Shen, Xuejiang Gu, Yiming Mu, Lulu Chen, Tianshu Zeng, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Guijun Qin, Qin Wan, Gang Chen, Xulei Tang, Zhengnan Gao, Ruying Hu, Zuojie Luo, Yingfen Qin, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Guixia Wang, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Yujin Zhu, Tao Yang, Huacong Deng, Jiajun Zhao, Yifang Zhang, Xingkun Xu, Huapeng Wei, Jie Zheng, Tiange Wang, Zhiyun Zhao, Guang Ning, Yuhong Chen, Weiqing Wang, Yufang Bi, Jieli Lu","doi":"10.1016/j.xcrm.2025.102372","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102372","url":null,"abstract":"<p><p>Obesity, a major public health challenge, is characterized by substantial phenotypic heterogeneity. Here, we employ the discriminative dimensionality reduction tree (DDRTree) method to routine clinical data from 18,733 Chinese individuals with obesity enrolled in the nationwide China Cardiometabolic Disease and Cancer Cohort (4C) study. We identify five distinct metabolic phenotypes, among which the phenotype characterized by hyperglycemia and insulin resistance exhibits a higher risk of glycemic deterioration, while the phenotype characterized by hypertension and dyslipidemia demonstrates an elevated risk of microvascular and macrovascular diseases. These findings are validated in an independent prospective cohort. Additionally, we reveal distinctive metabolomic features that contribute to the heterogeneity of obesity in the 4C study. To translate our findings into practice, we develop a user-friendly online tool to assess event risks in the obese population. Overall, our analysis illustrates the underlying phenotypic variations influencing subsequent obesity-related outcomes, emphasizing the importance of precision medicine in obesity management.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102372"},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173896","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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