{"title":"Co-targeting BMI1 and MYC to eliminate cancer stem cells in squamous cell carcinoma.","authors":"Zhen Qin, Shuo Liu, Yunfei Zheng, Yujia Wang, Yiwen Chen, Xin Peng, Lingfei Jia","doi":"10.1016/j.xcrm.2025.102077","DOIUrl":"10.1016/j.xcrm.2025.102077","url":null,"abstract":"<p><p>Bmi1<sup>+</sup> tumor cells act as cancer stem cells (CSCs) driving relapse and therapy resistance in head and neck squamous cell carcinoma (HNSCC). Although BMI1 inhibitors reduce CSCs, combined cisplatin treatment targeting non-stem tumor cells is more effective in eliminating CSCs. Non-stem tumor cells may revert to CSCs post-treatment. However, in vivo evidence and underlying mechanisms remain unclear. Here, we demonstrate that BMI1 inhibitors induce temporary tumor regression followed by relapse. Lineage tracing reveals that keratin 16-marked non-stem tumor cells revert to Bmi1<sup>+</sup> CSCs, which drive compensatory tumor growth after BMI1 targeting therapy. Mechanistically, BMI1 inhibitors activate DNA damage/nuclear factor κB (NF-κB) signaling and inflammatory cytokine secretion, subsequently stimulating myelocytomatosis viral oncogene homolog (MYC) expression in non-stem tumor cells to promote the reversion process. Genetic and pharmacological inhibition of MYC synergizes with BMI1 targeting, achieving sustained CSC eradication and relapse prevention. These findings provide insights into CSCs' plasticity and suggest dual BMI1/MYC blockade as an effective HNSCC treatment strategy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102077"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting STING antagonism in HSV-1: A peptide-based strategy to restore antiviral immunity and suppress viral pathogenesis.","authors":"Jiangwei Song, Mengzhou Xue, Chunfu Zheng","doi":"10.1016/j.xcrm.2025.102088","DOIUrl":"10.1016/j.xcrm.2025.102088","url":null,"abstract":"<p><p>Herpes simplex virus 1 (HSV-1) poses significant threats to human health. Wang et al.<sup>1</sup> show that the HSV-1 protein directly antagonizes stimulator of interferon genes (STING). A designed peptide derived from STING can restore virus-subverted immunity and inhibit HSV-1 replication and pathogenesis in mice.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 5","pages":"102088"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-01DOI: 10.1016/j.xcrm.2025.102096
Xiu-Feng Liu, Bin Song, Chang-Bin Sun, Qian Zhu, Jian-Hui Yue, Yu-Jing Liang, Jia He, Xi-Liang Zeng, Ye-Chi Qin, Qiu-Yan Chen, Hai-Qiang Mai, Xi Zhang, Jiang Li
{"title":"Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.","authors":"Xiu-Feng Liu, Bin Song, Chang-Bin Sun, Qian Zhu, Jian-Hui Yue, Yu-Jing Liang, Jia He, Xi-Liang Zeng, Ye-Chi Qin, Qiu-Yan Chen, Hai-Qiang Mai, Xi Zhang, Jiang Li","doi":"10.1016/j.xcrm.2025.102096","DOIUrl":"10.1016/j.xcrm.2025.102096","url":null,"abstract":"<p><p>Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has demonstrated clinical success in solid tumors. We analyze 47 TIL infusion products and 62 pretreatment tumor microenvironments (TMEs) from a randomized phase 2 clinical study of concurrent chemoradiotherapy plus TIL-ACT (NCT02421640). Using single-cell and bulk RNA sequencing along with flow cytometry, we identify 14 CD3<sup>+</sup> T cell clusters within 26 TIL infusion products: 11 CD3<sup>+</sup>CD8<sup>+</sup> TILs, 2 CD3<sup>+</sup>CD4<sup>+</sup> TILs, and 1 CD3<sup>+</sup>CD8<sup>-</sup>CD4<sup>-</sup> double-negative (DN) TIL. (DN) TILs, significantly associated with poor TIL-ACT outcomes, exhibit an activated regulatory T cell-like phenotype and include two CD56<sup>+</sup> and four CD56<sup>-</sup> subsets. Among them, CD56<sup>-</sup>KZF2<sup>+</sup> (DN) TILs are predominantly suppressive. (DN) TILs inhibit CD8<sup>+</sup> TIL expansion via Fas-FasL, transforming growth factor β (TGF-β), and interleukin (IL)-10 signaling. Distinct CD8<sup>+</sup> T subsets differentially impact on TIL-ACT outcomes, while 9 baseline TME gene signatures and 14 intracellular T cell genes hold prognostic value. Our findings identify predictive TIL subsets and biomarkers for TIL-ACT outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102096"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-06DOI: 10.1016/j.xcrm.2025.102121
Yan Xu, James Chih-Hsin Yang, Yanqiu Zhao, Ludovic Doucet, Jianying Zhou, Yongsheng Wang, David Planchard, Yun Fan, Bo Jin, Zhigang Han, Laurent Greillier, Julien Mazieres, Meili Sun, Ying Hu, Xia Song, Cuimin Ding, Lin Wu, Kejing Tang, Li Liang, Yu Yao, Ying Cheng, Yong He, Bruna Pellini Ferreira, François Ghiringhelli, Enriqueta Felip, Joaquim Bosch-Barrera, Anwen Liu, Yan Yu, Xiaorong Dong, Junzhen Gao, D Ross Camidge, Weiqi Nian, Chengzhi Zhou, Runxiang Yang, Thomas John, Bo Gao, Lyudmila Bazhenova, Misako Nagasaka, Jianghong Wang, Xiubao Ren, Fei Xu, Wen Li, Dahai Zhao, Huijie Wang, Si Sun, Jian'an Huang, Xuehua Zhu, Li Zheng, Pasi A Jänne, Mengzhao Wang
{"title":"Genetic biomarker study of sunvozertinib for clinical prognosis and prediction in NSCLC with EGFR exon 20 insertion mutation.","authors":"Yan Xu, James Chih-Hsin Yang, Yanqiu Zhao, Ludovic Doucet, Jianying Zhou, Yongsheng Wang, David Planchard, Yun Fan, Bo Jin, Zhigang Han, Laurent Greillier, Julien Mazieres, Meili Sun, Ying Hu, Xia Song, Cuimin Ding, Lin Wu, Kejing Tang, Li Liang, Yu Yao, Ying Cheng, Yong He, Bruna Pellini Ferreira, François Ghiringhelli, Enriqueta Felip, Joaquim Bosch-Barrera, Anwen Liu, Yan Yu, Xiaorong Dong, Junzhen Gao, D Ross Camidge, Weiqi Nian, Chengzhi Zhou, Runxiang Yang, Thomas John, Bo Gao, Lyudmila Bazhenova, Misako Nagasaka, Jianghong Wang, Xiubao Ren, Fei Xu, Wen Li, Dahai Zhao, Huijie Wang, Si Sun, Jian'an Huang, Xuehua Zhu, Li Zheng, Pasi A Jänne, Mengzhao Wang","doi":"10.1016/j.xcrm.2025.102121","DOIUrl":"10.1016/j.xcrm.2025.102121","url":null,"abstract":"<p><p>This is a report of biomarker analysis for sunvozertinib, a leading epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting EGFR exon 20 insertion mutation (exon20ins) non-small cell lung cancer (NSCLC). There is a positive correlation between positive EGFR exon20ins in plasma circulating tumor DNA (ctDNA) and advanced disease. Shorter progression-free survival and lower objective response rate (45.8% vs. 68.0%) were observed in patients with positive EGFR exon20ins compared to those with negative status. Droplet digital PCR analysis showed that the EGFR exon20ins allele in ctDNA decreased over time in 85.7% of patients, with the earliest clearance occurred after 1 week of sunvozertinib treatment. Acquired EGFR C797S is identified as a potential on-target resistance mutation to sunvozertinib. Finally, efforts are undertaken to investigate therapeutic approaches that aim to overcome the putative acquired resistance to sunvozertinib.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102121"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-08DOI: 10.1016/j.xcrm.2025.102127
James R Tribble, Vickie H Y Wong, Kelsey V Stuart, Glyn Chidlow, Alan Nicol, Anne Rombaut, Alessandro Rabiolo, Anh Hoang, Pei Ying Lee, Carola Rutigliani, Tim J Enz, Alessio Canovai, Emma Lardner, Gustav Stålhammar, Christine T O Nguyen, David F Garway-Heath, Robert J Casson, Anthony P Khawaja, Bang V Bui, Pete A Williams
{"title":"Dysfunctional one-carbon metabolism identifies vitamins B<sub>6</sub>, B<sub>9</sub>, B<sub>12</sub>, and choline as neuroprotective in glaucoma.","authors":"James R Tribble, Vickie H Y Wong, Kelsey V Stuart, Glyn Chidlow, Alan Nicol, Anne Rombaut, Alessandro Rabiolo, Anh Hoang, Pei Ying Lee, Carola Rutigliani, Tim J Enz, Alessio Canovai, Emma Lardner, Gustav Stålhammar, Christine T O Nguyen, David F Garway-Heath, Robert J Casson, Anthony P Khawaja, Bang V Bui, Pete A Williams","doi":"10.1016/j.xcrm.2025.102127","DOIUrl":"10.1016/j.xcrm.2025.102127","url":null,"abstract":"<p><p>Glaucoma, characterized by the loss of retinal ganglion cells (RGCs), is a leading cause of blindness for which there are no neuroprotective therapies. To explore observations of elevated homocysteine in glaucoma, we elevate vitreous homocysteine, which increases RGC death by 6% following ocular hypertension. Genetic association with higher homocysteine does not affect glaucoma-associated outcomes from the UK Biobank and serum homocysteine levels have no effect on glaucomatous visual field progression. This supports a hypothesis in which elevated homocysteine is a pathogenic, rather than causative, feature of glaucoma. Further exploration of homocysteine metabolism in glaucoma animal models demonstrates early and sustained dysregulation of genes involved in one-carbon metabolism and the interaction of essential cofactors and precursors (B<sub>6</sub>, B<sub>9</sub>, B<sub>12</sub>, and choline) in whole retina and optic nerve head and RGCs. Supplementing these provides neuroprotection in an acute model and prevents neurodegeneration and protects visual function in a chronic model of glaucoma.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102127"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-08DOI: 10.1016/j.xcrm.2025.102120
David J Park, Min Thura, Vi K Chiu, Brian Vicuna, Koon Hwee Ang, Blanca Sanchez, Pei Ling Chia, Kam Yew Kuan, Jie Li, Ke Zhang, Wei Hui Zheng, Matthew Chau Hsien Ng, Qi Zeng
{"title":"The PRL3-zumab paradigm: A multicenter, single-dose-level phase 2 basket clinical trial design of an unconventional cancer immunotherapy.","authors":"David J Park, Min Thura, Vi K Chiu, Brian Vicuna, Koon Hwee Ang, Blanca Sanchez, Pei Ling Chia, Kam Yew Kuan, Jie Li, Ke Zhang, Wei Hui Zheng, Matthew Chau Hsien Ng, Qi Zeng","doi":"10.1016/j.xcrm.2025.102120","DOIUrl":"10.1016/j.xcrm.2025.102120","url":null,"abstract":"<p><p>This Food and Drug Administration (FDA)-approved phase 2 basket trial has three highlights: (1) PRL3, an intracellular oncotarget that is highly (∼80.6%) expressed in multiple cancers; (2) PRL3-zumab, the first-in-class humanized antibody (immunoglobulin G1 [IgG1]) with high affinity to PRL3 (K<sub>d</sub> = 7.57 pM); and (3) proof of concept: targeting intracellular oncoprotein with antibody-based therapy. A full analysis set (FAS, 51 patients received ≥1 dose) is used for pharmacokinetic and safety studies. Out of FAS, 20 patients are eligible to constitute the efficacy evaluable set (EES). To circumvent the heterogeneities from different individuals/cancers, we propose single evaluable patient single cohort (SEPSC) and apply comparison using double stringent/rigorous controls with (1) historical progression-free survival (PFS) and (2) prior lines' PFS within the same patients. PRL3-zumab shows longer PFS than prior line(s) of anti-PD-(L)1 therapies. PRL3-zumab demonstrates excellent safety and clear clinical benefits in late-stage IV solid cancer patients. This trial is registered at ClinicalTrials.gov as NCT04452955.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102120"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rimjhim Agarwal, James Chang, Fernanda H Côrtes, Calvin Ha, John Villalpando, Izabella N Castillo, Rosa Isela Gálvez, Alba Grifoni, Alessandro Sette, Claudia M Romero-Vivas, Mark T Heise, Lakshmanane Premkumar, Andrew K Falconar, Daniela Weiskopf
{"title":"Chikungunya virus-specific CD4<sup>+</sup> T cells are associated with chronic chikungunya viral arthritic disease in humans.","authors":"Rimjhim Agarwal, James Chang, Fernanda H Côrtes, Calvin Ha, John Villalpando, Izabella N Castillo, Rosa Isela Gálvez, Alba Grifoni, Alessandro Sette, Claudia M Romero-Vivas, Mark T Heise, Lakshmanane Premkumar, Andrew K Falconar, Daniela Weiskopf","doi":"10.1016/j.xcrm.2025.102134","DOIUrl":"10.1016/j.xcrm.2025.102134","url":null,"abstract":"<p><p>Chikungunya virus (CHIKV) is a mosquito-borne virus that can cause chronic chikungunya virus disease (CHIKVD), which is characterized by persistent incapacitating arthralgia. Despite recurring CHIKV outbreaks and recent approval of a vaccine, the breadth and target of T cell responses in CHIKVD remain largely understudied. Here, we tested peripheral blood mononuclear cells (PBMCs) collected from CHIKV-infected individuals against overlapping peptide pools sequentially spanning the entire CHIKV proteome. We detected robust CHIKV-specific CD4<sup>+</sup>, but not CD8<sup>+</sup>, T cell responses in infected individuals. Individuals with chronic arthralgia displayed significantly higher CD4<sup>+</sup> T cell responses against nsP1, nsP2, and E2 proteins and exhibited a significantly lower Th1 CD4<sup>+</sup> T cell population, compared to individuals who had recovered. Additionally, CD4<sup>+</sup> T cells in chronic individuals were marked by a predominant production of tumor necrosis factor alpha (TNF-α). Overall, our work comprehensively characterizes T cell responses in CHIKVD in humans and provides insights into the role of T cells in CHIKVD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 5","pages":"102134"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"MMRNet: Ensemble deep learning models for predicting mismatch repair deficiency in endometrial cancer from histopathological images.","authors":"Li-Li Liu, Bing-Zhong Jing, Xuan Liu, Rong-Gang Li, Zhao Wan, Jiang-Yu Zhang, Xiao-Ming Ouyang, Qing-Nuan Kong, Xiao-Ling Kang, Dong-Dong Wang, Hao-Hua Chen, Zi-Han Zhao, Hao-Yu Liang, Ma-Yan Huang, Cheng-You Zheng, Xia Yang, Xue-Yi Zheng, Xin-Ke Zhang, Li-Jun Wei, Chao Cao, Hong-Yi Gao, Rong-Zhen Luo, Mu-Yan Cai","doi":"10.1016/j.xcrm.2025.102099","DOIUrl":"10.1016/j.xcrm.2025.102099","url":null,"abstract":"<p><p>Combining molecular classification with clinicopathologic methods improves risk assessment and chooses therapies for endometrial cancer (EC). Detecting mismatch repair (MMR) deficiencies in EC is crucial for screening Lynch syndrome and identifying immunotherapy candidates. An affordable and accessible tool is urgently needed to determine MMR status in EC patients. We introduce MMRNet, a deep convolutional neural network designed to predict MMR-deficient EC from whole-slide images stained with hematoxylin and eosin. MMRNet demonstrates strong performance, achieving an average area under the receiver operating characteristic curve (AUROC) of 0.897, with a sensitivity of 0.628 and a specificity of 0.949 in internal cross-validation. External validation using three additional datasets results in AUROCs of 0.790, 0.807, and 0.863. Employing a human-machine fusion approach notably improves diagnostic accuracy. MMRNet presents an effective method for identifying EC cases for confirmatory MMR testing and may assist in selecting candidates for immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102099"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-08DOI: 10.1016/j.xcrm.2025.102131
Antoine Jalil, Thomas Pilot, Thibaut Bourgeois, Aline Laubriet, Xiaoxu Li, Marc Diedisheim, Valérie Deckert, Charlène Magnani, Naig Le Guern, Jean-Paul Pais de Barros, Maxime Nguyen, Gaëtan Pallot, Adrien Vouilloz, Lil Proukhnitzky, François Hermetet, Virginie Aires, Eric Lesniewska, Laurent Lagrost, Johan Auwerx, Wilfried Le Goff, Nicolas Venteclef, Eric Steinmetz, Charles Thomas, David Masson
{"title":"Plasmalogen remodeling modulates macrophage response to cytotoxic oxysterols and atherosclerotic plaque vulnerability.","authors":"Antoine Jalil, Thomas Pilot, Thibaut Bourgeois, Aline Laubriet, Xiaoxu Li, Marc Diedisheim, Valérie Deckert, Charlène Magnani, Naig Le Guern, Jean-Paul Pais de Barros, Maxime Nguyen, Gaëtan Pallot, Adrien Vouilloz, Lil Proukhnitzky, François Hermetet, Virginie Aires, Eric Lesniewska, Laurent Lagrost, Johan Auwerx, Wilfried Le Goff, Nicolas Venteclef, Eric Steinmetz, Charles Thomas, David Masson","doi":"10.1016/j.xcrm.2025.102131","DOIUrl":"10.1016/j.xcrm.2025.102131","url":null,"abstract":"<p><p>Essential fatty acid metabolism in myeloid cells plays a critical but underexplored role in immune function. Here, we demonstrate that simultaneous inactivation of two key enzymes involved in macrophage polyunsaturated fatty acid (PUFA) metabolism-ELOVL5, which elongates long-chain PUFAs, and LPCAT3, which incorporates them into phospholipids-disrupts membrane organization by promoting the formation of cholesterol-enriched domains. This increases macrophage sensitivity to cytotoxic oxysterols and leads to more vulnerable atherosclerotic plaques with enlarged necrotic cores in a mouse model of atherosclerosis. In humans, analysis of 187 carotid plaques reveals a positive correlation between LPCAT3/ELOVL5-generated phospholipids-including arachidonate (C20:4 n-6)-containing ether lipids-and more stable plaque profiles. Additionally, Mendelian randomization analysis supports a causal relationship between LPCAT3 expression and reduced risk of ischemic stroke. Our findings uncover a regulatory circuit essential for PUFA-containing phospholipid generation in macrophages, positioning PUFA-containing ether lipids as promising biomarkers and therapeutic targets.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102131"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-04-28DOI: 10.1016/j.xcrm.2025.102094
Michael M Halassa, Michael J Frank, Philippa Garety, Dost Ongur, Raag D Airan, Gerard Sanacora, Kafui Dzirasa, Sahil Suresh, Susan M Fitzpatrick, Douglas L Rothman
{"title":"Developing algorithmic psychiatry via multi-level spanning computational models.","authors":"Michael M Halassa, Michael J Frank, Philippa Garety, Dost Ongur, Raag D Airan, Gerard Sanacora, Kafui Dzirasa, Sahil Suresh, Susan M Fitzpatrick, Douglas L Rothman","doi":"10.1016/j.xcrm.2025.102094","DOIUrl":"10.1016/j.xcrm.2025.102094","url":null,"abstract":"<p><p>Modern psychiatry faces challenges in translating neurobiological insights into treatments for severe illnesses. The mid-20th century witnessed the rise of molecular mechanisms as pathophysiological and treatment models, with recent holistic proposals keeping this focus unaltered. In this perspective, we explore how psychiatry can utilize systems neuroscience to develop a vertically integrated understanding of brain function to inform treatment. Using schizophrenia as a case study, we discuss scale-related challenges faced by researchers studying molecules, circuits, networks, and cognition and clinicians operating within existing frameworks. We emphasize computation as a bridging language, with algorithmic models like hierarchical predictive processing offering explanatory potential for targeted interventions. Developing such models will not only facilitate new interventions but also optimize combining existing treatments by predicting their multi-level effects. We conclude with the prognosis that the future is bright, but that continued investment in research closely driven by clinical realities will be critical.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102094"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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