{"title":"Tumor-colonizing Bifidobacterium dentium promotes tumor progression and chemotherapy resistance via MMP3 and GABA-FOXA2-P-gp axis.","authors":"Xiaoyun Pan, Shuyi Luo, Shuheng Dou, Yiqiu Li, Chanci Qiu, Qiao Pan, Xiaoshi Zhang, Ge Zhang, Songhe Guo","doi":"10.1016/j.xcrm.2026.103142","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103142","url":null,"abstract":"<p><p>The intratumoral microbiota plays a crucial role in cancer pathogenesis; however, the specific members involved and their mechanisms remain incompletely defined. Here, we identify Bifidobacterium dentium (B. dentium ) as a tumor-associated bacterium enriched in fecal samples from patients with melanoma and colorectal cancer (CRC) and detectable in human melanoma and CRC tissues. High intratumoral B. dentium abundance correlates with poorer survival in CRC patients. In mouse models, subgingival administration of live B. dentium enables tumor homing and accelerated CT26 and B16F10 tumor growth, including in an orthotopic CT26 colorectal tumor model. Mechanistically, B. dentium invades tumor cells, promotes proliferation through Akt/ERK activation, enhances metastatic potential through MMP3 induction, and increases resistance to key chemotherapeutic agents. B. dentium-derived GABA activates FOXA2-dependent P-gp upregulation, contributing to chemotherapy resistance. These findings establish B. dentium as a niche-dependent pro-tumoral pathobiont and a potential target for improving cancer treatment response.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103142"},"PeriodicalIF":14.0,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377620","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}
Kerryan Ashley, Alicia Ding, Mohammad Arammash, Krishna Iyer, Kishu Ranjan, Barani Kumar Rajendran, Boyu Huang, Daniel Boiarsky, Roy Herbst, Sarah Goldberg, Kurt A Schalper
{"title":"The CD39/CD73 adenosinergic pathway is increased by proinflammatory states and modified by chemo-radiation in human non-small cell lung cancer.","authors":"Kerryan Ashley, Alicia Ding, Mohammad Arammash, Krishna Iyer, Kishu Ranjan, Barani Kumar Rajendran, Boyu Huang, Daniel Boiarsky, Roy Herbst, Sarah Goldberg, Kurt A Schalper","doi":"10.1016/j.xcrm.2026.103139","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103139","url":null,"abstract":"<p><p>Recent clinical trials show prominent anti-tumor activity of CD73-blocking antibodies in combination with programmed death-ligand 1 (PD-L1) antagonists in a subset of patients with resectable non-small cell lung cancer (NSCLC), which highlights the need to understand the properties of the CD39/CD73 pathway in human lung malignancies and its modulation by other anti-cancer therapies. To address this, we study the distribution, biological context, spatial heterogeneity, clinical significance, and modulation of CD39/CD73 using multiplexed quantitative immunofluorescence and spatial transcriptomics analysis of multiple NSCLC patient cohorts, as well as in vitro experiments of cultured NSCLC cells. Our results reveal an asymmetric distribution of the CD39/CD73 pathway within the tumor microenvironment, preferential expression in lung adenocarcinomas with elevated PD-L1 and effector T cell infiltration or lacking STK11/KEAP1 mutations, limited intratumor spatial heterogeneity, and differential modulation of cancer cell CD73 by proinflammatory cytokines and systemic radio-chemotherapy. Collectively, our results can inform optimal design of therapeutic interventions and patient selection strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103139"},"PeriodicalIF":14.0,"publicationDate":"2026-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149377619","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":"Spatiotemporal dynamic evolution of the tumor microenvironment during neoadjuvant immunotherapy for bladder cancer.","authors":"Jiao Hu, Yifan Liu, Minfeng Chen, Jiantu Ou, Tongchen He, Jinhui Liu, Minghui Hu, Bohan Zhou, Huihuang Li, Luzhe Yan, Jiatong Xiao, Zhenyu Nie, Zhiyong Cai, Peihua Liu, Dingshan Deng, Yunbo He, Benyi Fan, Zhenyu Ou, Ruizhe Wang, Guanghui Gong, Xiao Guan, Shiyu Tong, Yangle Li, Wei He, Zefu Liu, Yuanqing Dai, Bolong Liu, Xiaogen Kuang, Tao Guo, Lunquan Sun, Xiaohua Yao, Junhao Yu, Hengyun Wang, Jinbo Chen, Xiongbing Zu","doi":"10.1016/j.xcrm.2026.103140","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103140","url":null,"abstract":"<p><p>We characterize the spatiotemporal dynamics of the tumor microenvironment (TME) in bladder cancer (BLCA) samples before and after neoadjuvant immunotherapy in a multicenter real-world cohort (n = 606). We identify two distinct differentiation outcomes in BLCA epithelial cells: sensitivity and resistance to immunotherapy. Additionally, we identify SERPINH1 as a common target of acquired immunotherapy resistance in BLCA. Furthermore, we characterize an immunotherapy-induced tumor-myeloid barrier, which leads to an excluded immune phenotype and immunotherapy resistance. Finally, we identify T cell terminal exhaustion and a senescent inflammatory cancer-associated fibroblast phenotype as key factors contributing to immunotherapy resistance. Collectively, we reveal the dynamic phenotypic evolution of the TME in BLCA during neoadjuvant immunotherapy and identify the characteristics of residual lesions after immunotherapy. These findings enrich our understanding of immunotherapy resistance in BLCA and contribute to developing combination therapies to improve patient prognosis.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103140"},"PeriodicalIF":14.0,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149357195","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}
Yuanqin Zhang, Xia Liu, Yixuan Xie, Lei Zhao, Myung Sik Jeon, Lisha Ai, Jingqin Luo, David A Ford, Hazar Abusalamah, R Alex Harbison, Cody Huffman, Jialin Guo, Iris He, Allison Mulvehill, Craig A Buchman, Sidharth V Puram, Benjamin A Garcia, Mark A Varvares, Marco Colonna, Guangyong Peng
{"title":"Senescent T cells within the tumor microenvironment are a potent driver for tumor growth, stemness, and chemotherapy resistance.","authors":"Yuanqin Zhang, Xia Liu, Yixuan Xie, Lei Zhao, Myung Sik Jeon, Lisha Ai, Jingqin Luo, David A Ford, Hazar Abusalamah, R Alex Harbison, Cody Huffman, Jialin Guo, Iris He, Allison Mulvehill, Craig A Buchman, Sidharth V Puram, Benjamin A Garcia, Mark A Varvares, Marco Colonna, Guangyong Peng","doi":"10.1016/j.xcrm.2026.103141","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103141","url":null,"abstract":"<p><p>T cell senescence is an important dysfunctional state associated with tumor progression, but whether senescent T (Tsen) cells directly reprogram tumor cell behavior remains unknown. Here, single-cell transcriptomic analyses identify abundant Tsen cells across breast, colorectal, and lung cancers. Tsen cells actively promote tumor growth, metastasis, stemness, and chemotherapy resistance by reprogramming tumor cells in vitro and in vivo. Mechanistically, lipid-enriched senescence-associated secretory phenotypes (SASPs) from Tsen cells drive metabolic remodeling and activate STAT1/STAT3 signaling in tumor cells, establishing a pro-tumorigenic state. Therapeutically, depletion of Tsen cells or disruption of tumor lipid metabolic reprogramming suppresses Tsen-mediated tumor progression and metastasis in vivo. Our findings establish Tsen cells as active orchestrators of tumor cell biological functions through lipid-rich SASP-dependent intercellular communication and reveal a previously unrecognized mechanism linking immune senescence to cancer progression. Targeting Tsen cells or their metabolic crosstalk with tumor cells can enhance anti-tumor immunity and improve therapeutic responses.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103141"},"PeriodicalIF":14.0,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149357194","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}
Mickael Tordjman, Alexander Dimitrakakis, Murat Yuce, Mira M Liu, Anis Meribout, Zelong Liu, Hamza Ahmed, Ian Bolger, Philip M Robson, Alexis Colvin, Mingqian Huang, Charbel Ishak, Chaojun Zhang, Carolyn Horst, Haidara Almansour, Amish Doshi, Giuseppe Petralia, Bachir Taouli, Timothy Deyer, Zahi A Fayad, Hao-Chih Lee, Xueyan Mei
{"title":"Unimodal imaging foundation models and vision-language models in MRI: A systematic review of emerging methods and clinical applications.","authors":"Mickael Tordjman, Alexander Dimitrakakis, Murat Yuce, Mira M Liu, Anis Meribout, Zelong Liu, Hamza Ahmed, Ian Bolger, Philip M Robson, Alexis Colvin, Mingqian Huang, Charbel Ishak, Chaojun Zhang, Carolyn Horst, Haidara Almansour, Amish Doshi, Giuseppe Petralia, Bachir Taouli, Timothy Deyer, Zahi A Fayad, Hao-Chih Lee, Xueyan Mei","doi":"10.1016/j.xcrm.2026.103134","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103134","url":null,"abstract":"<p><p>Artificial intelligence in medical imaging is shifting from task-specific algorithms toward adaptable foundation models (FMs) and vision-language models (VLMs). However, applying these models to MRI remains challenging because clinical interpretation requires integrating multi-parametric, volumetric imaging across multiple sequences with clinical context. This systematic review evaluates 35 studies on unimodal FMs and multimodal VLMs in MRI, summarizing emerging architectures, downstream applications, and challenges to clinical translation. Current research is concentrated in neuroimaging, with diagnostic classification representing the most mature application. Segmentation and outcome prediction also show promise, whereas automated report generation remains limited by poor clinical fidelity despite strong linguistic fluency. Broader adoption is hindered by heterogeneous MRI acquisition, limited large-scale paired image-text datasets, and inadequate safety-focused evaluation metrics. Advancing clinical translation will require standardized multicenter datasets, stronger integration with electronic health records and pathology, robust evaluation frameworks, and improved model explainability.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103134"},"PeriodicalIF":14.0,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149357196","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}
Arushi Kohli, Bridget M Hron, Cara B Ebbeling, Mildred M Reyes, Matthew Quealy, Thomas Gurry, Le Thanh Tu Nguyen, Eric J Alm, David S Ludwig, Yanjia J Zhang
{"title":"Effects of dietary carbohydrate-to-fat ratio on the gut microbiome following weight loss.","authors":"Arushi Kohli, Bridget M Hron, Cara B Ebbeling, Mildred M Reyes, Matthew Quealy, Thomas Gurry, Le Thanh Tu Nguyen, Eric J Alm, David S Ludwig, Yanjia J Zhang","doi":"10.1016/j.xcrm.2026.103137","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103137","url":null,"abstract":"<p><p>Reducing dietary carbohydrates can improve metabolic health, yet the precise influence of carbohydrate restriction on the gut microbiome remains uncertain. Here, we report an ancillary study to the Framingham State Food Study, or FS(2), a controlled, randomized feeding trial involving adults with overweight and obesity. After a calorie-restriction phase to induce weight loss, we randomized participants to diets varying in energy from carbohydrate and fat (low-carb: 20% carb, 60% fat; moderate-carb: 40% carb, 40% fat; high-carb: 60% carb, 20% fat) for weight-loss maintenance for 20 weeks. Weight loss results in significant microbiome shifts, mirroring known associations. We do not detect compositional changes in the microbiome when diets vary carbohydrate-to-fat ratio, while controlling for other potentially confounding dietary factors. Changes in Shuttleworthia abundance correlate positively with maintenance of total energy expenditure following weight loss, suggesting a link between the gut microbiome and energy metabolism.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103137"},"PeriodicalIF":14.0,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149357192","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}
Vinicius A Schoeps, Pavan Bhargava, Gina Chang, Danielle J Caruso, Dohee Kim, Akash Virupakshaiah, Janet Chong, Gregory Aaen, Jennifer S Graves, Leslie A Benson, Mark P Gorman, Mary Rensel, Aaron W Abrams, Soe S Mar, Timothy Lotze, Tanuja Chitnis, Amy T Waldman, Lauren B Krupp, Moses Rodriguez, Jan-Mendelt Tillema, John W Rose, Teri Schreiner, T Charles Casper, Helen Tremlett, John W Newman, Kamil Borkowski, Emmanuelle Waubant
{"title":"Propionate, a short-chain fatty acid, is associated with disease activity in pediatric-onset multiple sclerosis.","authors":"Vinicius A Schoeps, Pavan Bhargava, Gina Chang, Danielle J Caruso, Dohee Kim, Akash Virupakshaiah, Janet Chong, Gregory Aaen, Jennifer S Graves, Leslie A Benson, Mark P Gorman, Mary Rensel, Aaron W Abrams, Soe S Mar, Timothy Lotze, Tanuja Chitnis, Amy T Waldman, Lauren B Krupp, Moses Rodriguez, Jan-Mendelt Tillema, John W Rose, Teri Schreiner, T Charles Casper, Helen Tremlett, John W Newman, Kamil Borkowski, Emmanuelle Waubant","doi":"10.1016/j.xcrm.2026.103136","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103136","url":null,"abstract":"<p><p>Short-chain fatty acids (SCFAs), metabolites found in fermented foods and produced by colonic bacterial fermentation of dietary fibers, may mediate gut-brain axis crosstalk influencing the course of multiple sclerosis (MS). In this study, SCFAs are measured in plasma and paired stool samples by targeted mass spectrometry in a large cohort of deeply phenotyped individuals shortly after MS onset. Propionate is consistently associated with a protective effect on three clinical and imaging activity-related outcomes. Findings are reproduced in an equally large external cohort for plasma and stool measurements. Despite the correlation between plasma SCFAs and SCFA-producing gut microbial taxa, propionate levels are not correlated with dietary fiber, suggesting that intake may not be sufficient to modulate its levels and ensuing inflammation. In conclusion, propionate is consistently associated with lower disease activity, and exogenous administration may be more likely than fiber supplementation to confer protective effects on MS activity in proof-of-concept clinical trials.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103136"},"PeriodicalIF":14.0,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149357193","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}
Joanne Marie M Del Rosario, Sneha Vishwanath, Simon D W Frost, Sneha B Sujit, Sruthika K Ashokan, Robert Vendramelli, Matteo Ferrari, George W Carnell, Lucrezia Vianello, Matteo Pagliari, Sami Ramzi, Valentina Maria Panzarin, Elisa Mazzacan, Andrea Fortin, Marta Vascellari, Thang Truong, Paul Tonks, Ana Liza Ortiz, Chloe Qingzhou Huang, Sebastian Einhauser, Michael Schachtner, Benedikt Asbach, Daniel Matthew L Storisteanu, Nigel J Temperton, Matthew N Davies, David Moss, Rebecca Kinsley, Ralf Wagner, Darwyn Kobasa, Francesco Bonfante, Jonathan L Heeney
{"title":"Broad vaccine protection against globally diverse influenza A/H5Nx viruses.","authors":"Joanne Marie M Del Rosario, Sneha Vishwanath, Simon D W Frost, Sneha B Sujit, Sruthika K Ashokan, Robert Vendramelli, Matteo Ferrari, George W Carnell, Lucrezia Vianello, Matteo Pagliari, Sami Ramzi, Valentina Maria Panzarin, Elisa Mazzacan, Andrea Fortin, Marta Vascellari, Thang Truong, Paul Tonks, Ana Liza Ortiz, Chloe Qingzhou Huang, Sebastian Einhauser, Michael Schachtner, Benedikt Asbach, Daniel Matthew L Storisteanu, Nigel J Temperton, Matthew N Davies, David Moss, Rebecca Kinsley, Ralf Wagner, Darwyn Kobasa, Francesco Bonfante, Jonathan L Heeney","doi":"10.1016/j.xcrm.2026.103131","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103131","url":null,"abstract":"<p><p>Influenza A/H5Nx viruses continue to diversify and undergo gene reassortment as they infect avian and mammalian hosts worldwide. The severity of human infections varies substantially between different H5 clades and neuraminidase (NA) reassortants, creating unpredictable pandemic risk. Existing H5 vaccines, typically based on a single hemagglutinin (HA) strain, cannot keep pace with this natural variation. To address this problem, we computationally engineer HA, NA, and M2 antigens representing the global antigenic space of circulating H5Nx viruses, prioritizing N1 and N6 subtypes associated with the highest threat in humans. The resulting digitally immune-optimized mRNA vaccine, DVX-panH5Nx, elicits broad HA neutralization and NA inhibition across divergent clades in mice and ferrets. Compared to WHO candidate vaccine viruses (CVVs), DVX-panH5Nx confers superior protection against antigenically distinct H5N1 challenges spanning two decades of viral evolution, demonstrating that computationally designed multivalent antigen vaccines can overcome natural influenza diversification and provide a scalable strategy for pre-pandemic preparedness.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103131"},"PeriodicalIF":14.0,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341046","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}
Peilong Li, Yan Xie, Yu Zhao, Qiuchen Qi, Shujun Zhang, Zhijun Zhang, Chunhai Gao, Kai Liu, Yue Meng, Peipei Mou, Kun Li, Linlin Qu, Daolin Tang, Chuanxin Wang, Juan Li, Lutao Du
{"title":"A peripheral blood mononuclear cell DNA methylation-based risk stratification tool for esophageal squamous cell carcinoma.","authors":"Peilong Li, Yan Xie, Yu Zhao, Qiuchen Qi, Shujun Zhang, Zhijun Zhang, Chunhai Gao, Kai Liu, Yue Meng, Peipei Mou, Kun Li, Linlin Qu, Daolin Tang, Chuanxin Wang, Juan Li, Lutao Du","doi":"10.1016/j.xcrm.2026.103132","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103132","url":null,"abstract":"<p><p>Early detection of esophageal squamous cell carcinoma is essential for improving survival, but reliance on endoscopy limits feasibility for population-wide screening. We developed ESCCseeker, a minimally invasive risk stratification tool based on peripheral blood mononuclear cells' DNA methylation. In a two-stage multicenter study in China, genome-wide profiling identifies distinct methylation markers between ESCC patients and controls. In the development and verification cohort, machine learning yields a model integrating eight differentially methylated positions with age, gender, SCC-Ag, and CYFRA21-1. ESCCseeker demonstrates robust performance (AUC: 0.987 training, 0.966 test, 0.943 verification), outperforming conventional biomarkers. In a prospective multicenter cohort, the predefined cutoff stratifies individuals into low- and high-risk groups. Restricting endoscopy to high-risk individuals reduces the number of endoscopies needed from 25.02 to 4.78, avoiding 83% of unnecessary procedures while preserving >90% detection sensitivity. These findings establish ESCCseeker as a reliable pre-endoscopic triage tool that minimizes unnecessary invasive procedures and prioritizes high-risk individuals. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR2500095967).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103132"},"PeriodicalIF":14.0,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341044","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}
Ole Isacson, Li-Huei Tsai, Leyla Akay, Frances Platt, Penelope Hallett
{"title":"Lipid homeostasis and cellular metabolism in neurodegenerative diseases: A maturing framework to guide therapeutic development.","authors":"Ole Isacson, Li-Huei Tsai, Leyla Akay, Frances Platt, Penelope Hallett","doi":"10.1016/j.xcrm.2026.103130","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103130","url":null,"abstract":"<p><p>Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies have long been viewed through the lens of protein aggregation. Emerging evidence, however, highlights lipid transfer, load, metabolism, and cellular homeostasis as upstream drivers of pathology. This perspective integrates established neurobiological, genetic, and mechanistic evidence of lipid dysfunction and outlines how these pathways can guide patient stratification, biomarker discovery, and therapeutic development. Of critical importance, lipid transport and lysosomal and trafficking networks are at the center of cholesterol regulation, glycosphingolipid clearance, endolysosomal function, and neuron-glia lipid exchange across genetic and sporadic neurodegenerative diseases. We present an integrated framework where correcting lipid imbalances and metabolic dysregulation may complement or obviate protein-targeted approaches, creating more precise clinical trials and combination strategies. By re-centering the therapeutic focus on lipid and cellular metabolism, we aim to catalyze translational advances in neurodegenerative disease treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103130"},"PeriodicalIF":14.0,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341049","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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