EBioMedicine最新文献

{"title":"LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation.","authors":"Di Cheng, Junge Deng, Bin Zhang, Xiaoyu He, Zhe Meng, Guolin Li, Huilin Ye, Shangyou Zheng, Lusheng Wei, Xiaogeng Deng, Rufu Chen, Jiajia Zhou","doi":"10.1016/j.ebiom.2025.105623","DOIUrl":"10.1016/j.ebiom.2025.105623","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105623"},"PeriodicalIF":9.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663003","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":"COVID-19 convalescent plasma in immunocompromised COVID-19 patients: more certainty and clarity are added to a complex evidence base.","authors":"Hyunah Yoon, Liise-Anne Pirofski","doi":"10.1016/j.ebiom.2025.105654","DOIUrl":"10.1016/j.ebiom.2025.105654","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105654"},"PeriodicalIF":9.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663002","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":"Clinical outcomes and genomic profiles of MAP2K1-mutated primary cutaneous melanocytic tumours.","authors":"Chiel F Ebbelaar, Anne M L Jansen, Leonie C M Speet, Frans Schutgens, Sietske Zoetemeyer, Anne-Marie Cleton-Jansen, Marijke R van Dijk, Gerben E Breimer, Lourens T Bloem, Wendy W J de Leng, Remco van Doorn, Karijn P M Suijkerbuijk, Anne M R Schrader, Willeke A M Blokx","doi":"10.1016/j.ebiom.2025.105643","DOIUrl":"10.1016/j.ebiom.2025.105643","url":null,"abstract":"<p><strong>Background: </strong>Primary cutaneous melanocytic tumours harbouring MAP2K1 mutations without second-hit genomic alterations represent a subclass of neoplasms with poorly understood biological behaviour. This study aimed to investigate the clinical outcomes and genomic characteristics of these tumours.</p><p><strong>Methods: </strong>This cohort study included primary cutaneous melanocytic tumours with MAP2K1 mutations from patients at two academic centres (Leiden University Medical Centre and University Medical Centre Utrecht). These mutations were categorised into three functional classes: Class I (RAF-dependent), Class II (RAF-regulated), and Class III (RAF-independent). Tumours underwent histopathological evaluation, next-generation sequencing (NGS), and copy number variation (CNV) analysis and were categorised as non-melanoma or melanoma. Clinical outcomes were assessed for each mutation class during follow-up visits and through the Dutch Pathology Database (PALGA) using the composite outcome of metastatic melanoma (recurrence, metastasis, or melanoma-related death).</p><p><strong>Findings: </strong>A total of 102 patients were included, with tumours classified as melanoma in 52 (51%) and non-melanoma in 50 (49%). The tumours displayed spitzoid histomorphology in over two-thirds of cases and harboured 31 distinct MAP2K1 mutations: 20 Class I (19.6%), 56 Class II (54.9%), and 26 Class III (25.5%). Class I mutations exclusively co-occurred with BRAF or NRAS mutations, while Class II and III mutations often acted as sole tumour drivers. Of the tumours with Class I mutations, 95% were classified as melanoma, which was less frequently the case for Class II (risk ratio [RR] 0.43 [95% CI: 0.31-0.60], p < 0.001) and Class III mutations (RR 0.40 [95% CI: 0.25-0.67], p < 0.001). MAP2K1 mutation Class and TERT-p mutation status were independent predictors for the composite outcome. Compared to Class I mutations, Class II mutations were negatively associated with the composite outcome (odds ratio [OR] 0.16 [95% CI: 0.03-0.75], p = 0.03), whereas Class III mutations were not associated (OR 0.31 [95% CI: 0.05-1.54], p = 0.16). TERT-p mutations were positively associated with the composite outcome (OR 23.1, 95% CI: 3.99-439.8, p < 0.005).</p><p><strong>Interpretation: </strong>Class I MAP2K1 mutations typically occur alongside other MAPK pathway mutations and may contribute to aggressive melanoma behaviour. In contrast, Class II and III MAP2K1 mutations can independently drive melanocytic tumourigenesis with a potential for metastasis, aligning with conventional melanomagenesis pathways, despite their frequent spitzoid histomorphology.</p><p><strong>Funding: </strong>This research was supported by the Hanarth Fund.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105643"},"PeriodicalIF":9.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662935","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":"Corrigendum to \"Yield of clinical metagenomics: insights from real-world practice for tissue infections\" [eBioMedicine 111(2025), 105536].","authors":"Hui Tang, Yuqing Chen, Xinyan Tang, Muyun Wei, Juan Hu, Xuan Zhang, Dairong Xiang, Qing Yang, Dongsheng Han","doi":"10.1016/j.ebiom.2025.105574","DOIUrl":"10.1016/j.ebiom.2025.105574","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105574"},"PeriodicalIF":9.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663000","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":"Anserine reduces mortality in experimental sepsis by preventing methylglyoxal-induced capillary leakage.","authors":"Thomas Schmoch, Nadia Gallenstein, Verena Peters, Maria Bartosova, Florian Uhle, Laura Kummer, Anian Mair, Ute Krauser, Manuel Feisst, Peter P Nawroth, Markus A Weigand, Claus Peter Schmitt, Thorsten Brenner","doi":"10.1016/j.ebiom.2025.105644","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105644","url":null,"abstract":"<p><strong>Background: </strong>We previously identified methylglyoxal as a biomarker for early identification and outcome prediction in human sepsis. We hypothesised that methylglyoxal causally impacts disease severity, and the methylglyoxal-scavenging dipeptide anserine can attenuate the detrimental effects of methylglyoxal.</p><p><strong>Methods: </strong>Using a translational approach, secondary analyses of two observational trials were performed to test the initial hypotheses. Afterwards, these results were re-evaluated in different murine models of experimental sepsis in vivo. The detrimental effects of methylglyoxal as well as the underlying mechanisms were further assessed in vitro using transendothelial electrical resistance measurements, fluorescence-activated cell sorting analyses, cytokine assays, gene expression analyses, and enzyme activity assays, as well as immunofluorescence and immunohistochemistry staining.</p><p><strong>Findings: </strong>The secondary analyses confirmed methylglyoxal as an independent marker associated with increased mortality within the first 48 h after sepsis onset and high catecholamine and fluid requirements in the first 24 h after sepsis onset. In the sepsis models, methylglyoxal-derived carbonyl stress significantly contributed to the development of capillary leakage by disrupting endothelial barrier-forming proteins. Mechanistically, a pathway involving the receptor of advanced glycation end products and mitogen-activated protein kinase was identified. The methylglyoxal-scavenging dipeptide anserine (β-alanyl-N-methylhistidine) reduced methylglyoxal-induced advanced glycation end-product formation and disruptions of junctional complexes in vitro. Moreover, anserine reduced capillary leakage and mortality in vivo.</p><p><strong>Interpretation: </strong>Methylglyoxal causally contributes to capillary leak formation and mortality in experimental sepsis, which can be mitigated by anserine. Therefore, anserine represents an innovative therapeutic option for the treatment of septic shock.</p><p><strong>Funding: </strong>German Research Foundation (grant number BR 4144/2-1).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105644"},"PeriodicalIF":9.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662913","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, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting.","authors":"Michele Tameris, Virginie Rozot, Claire Imbratta, Hennie Geldenhuys, Simon C Mendelsohn, Angelique Kany Kany Luabeya, Justin Shenje, Nicolette Tredoux, Michelle Fisher, Humphrey Mulenga, Nicole Bilek, Carly Young, Ashley Veldsman, Natasja Botes, Jelle Thole, Bernard Fritzell, Rajat Mukherjee, Ingrid Murillo Jelsbak, Esteban Rodriguez, Eugenia Puentes, Juana Doce, Dessislava Marinova, Jesús Gonzalo-Asensio, Nacho Aguilo, Carlos Martin, Thomas J Scriba, Mark Hatherill","doi":"10.1016/j.ebiom.2025.105628","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105628","url":null,"abstract":"<p><strong>Background: </strong>Safer and more effective tuberculosis (TB) vaccines than Bacille Calmette Guérin (BCG) are needed. We evaluated the safety, reactogenicity, and immunogenicity of three dose levels of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine, MTBVAC, compared to BCG, in South African infants.</p><p><strong>Methods: </strong>Healthy, HIV-unexposed, BCG-naïve infants were randomised to receive a single intradermal dose of BCG (2.5 × 10⁵ CFU, n = 24) or MTBVAC (2.5 × 10⁴, 2.5 × 10⁵, or 2.5 × 10⁶ CFU, each n = 25). Safety endpoints were solicited systemic, solicited injection site, and unsolicited adverse events (AE), and serious AE (SAE). Immunogenicity was measured using interferon-γ release assay (IGRA) and whole blood intracellular cytokine staining assay. Follow-up was 12 months post-vaccination.</p><p><strong>Findings: </strong>Ninety-nine infants were enrolled between 18 February 2019 and 08 March 2021. Seventy-eight infants experienced reactogenicity AE (all mild except one grade 2 erythema). Induration, swelling, and erythema were more frequent as MTBVAC dose increased. All reactogenicity events were less frequent in infants receiving MTBVAC 2.5 × 10⁵ CFU compared with BCG. Twelve infants (three BCG and nine MTBVAC recipients) experienced 14 vaccine-unrelated SAE, including one death due to bronchopneumonia (MTBVAC recipient). Eight infants were treated for unconfirmed pulmonary TB (four BCG and four MTBVAC 2.5 × 10⁴ CFU recipients); one BCG recipient was treated for unconfirmed TB meningitis. MTBVAC was immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T cells, which peaked at Day 56. The 2.5 × 10⁵ and 2.5 × 10⁶ CFU MTBVAC doses induced similar response magnitudes and were more immunogenic than BCG. Day 56 IGRA conversion was observed in 61 (87.4%) infants receiving any MTBVAC dose, but only 28 (42.4%) remained positive by Day 365.</p><p><strong>Interpretation: </strong>MTBVAC appeared safe, well-tolerated, and immunogenic at doses between 2.5 × 10⁴ and 2.5 × 10⁶ CFU in South African infants. The 2.5 × 10⁵ CFU MTBVAC dose, being less reactogenic and more immunogenic than BCG, was selected for a multi-centre, phase 3 trial.</p><p><strong>Funding: </strong>This trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105628"},"PeriodicalIF":9.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656558","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":"Large-scale computational modelling of H5 influenza variants against HA1-neutralising antibodies.","authors":"Colby T Ford, Shirish Yasa, Khaled Obeid, Rafael Jaimes, Phillip J Tomezsko, Sayal Guirales-Medrano, Richard Allen White, Daniel Janies","doi":"10.1016/j.ebiom.2025.105632","DOIUrl":"10.1016/j.ebiom.2025.105632","url":null,"abstract":"<p><strong>Background: </strong>The United States Department of Agriculture has recently released reports that show samples collected from 2022 to 2025 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds. Up to February 2025, the United States Centres for Disease Control and Prevention reports that there have been 67 humans infected with H5N1 since 2024 with 1 death. The broader potential impact on human health remains unclear.</p><p><strong>Methods: </strong>In this study, we computationally model 1804 protein complexes consisting of various H5 isolates from 1959 to 2024 against 11 haemagglutinin domain 1 (HA1)-neutralising antibodies. This was performed using AI-based protein folding and physics-based simulations of the antibody-antigen interactions. We analysed binding affinity changes over time and across various antibodies using multiple biochemical and biophysical binding metrics.</p><p><strong>Findings: </strong>This study shows a trend of weakening binding affinity of existing antibodies against H5 isolates over time, indicating that the H5N1 virus is evolving immune escape from our therapeutic and immunological defences. We also found that based on the wide variety of host species and geographic locations in which H5N1 was observed to have been transmitted from birds to mammals, there is not a single central reservoir host species or location associated with H5N1's spread.</p><p><strong>Interpretation: </strong>These results indicate that the virus has potential to move from epidemic to pandemic status. This study illustrates the value of high-performance computing to rapidly model protein-protein interactions and viral genomic sequence data at-scale for functional insights into medical preparedness.</p><p><strong>Funding: </strong>No external funding was used in this study.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105632"},"PeriodicalIF":9.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656556","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":"Next-generation diagnostics of bloodstream infections enabled by rapid whole-genome sequencing of bacterial cells purified from blood cultures.","authors":"Vincenzo Di Pilato, Chiara Bonaiuto, Fabio Morecchiato, Alberto Antonelli, Tommaso Giani, Gian Maria Rossolini","doi":"10.1016/j.ebiom.2025.105633","DOIUrl":"10.1016/j.ebiom.2025.105633","url":null,"abstract":"<p><strong>Background: </strong>Blood culture (BC) remains the cornerstone for diagnosis of bloodstream infections (BSI), but the long turn-around time (TAT) hampers timely selection of appropriate chemotherapy. Novel molecular approaches have been developed to provide faster results but are also affected by limitations. We developed a analytical workflow named LC-WGS (Whole-Genome Sequencing of Liquid Colony) for rapid whole-genome sequencing-based diagnosis of BSI, evaluating its accuracy performance over standard of care (SoC) diagnostic procedures.</p><p><strong>Methods: </strong>A total of 85 prospectively collected positive BC were processed in parallel with SoC (subculturing, identification by MALDI-ToF, antimicrobial susceptibility testing by reference broth microdilution, usage of syndromic panels) and LC-WGS, which relied on automated purification of microbial cells (Qvella FAST system, Qvella Corp.), DNA purification, and real-time sequencing with the Oxford Nanopore MinION. A streamlined analysis pipeline was designed for pathogen identification (Kraken2), detection of resistance markers (KmerResistance, AMRFinderPlus), virulome profiling (abricate, VFDB), phylogenetic analysis (snippy, IQ-TREE), and pathogen subtyping (Meningotype).</p><p><strong>Findings: </strong>Compared with SoC, LC-WGS returned accurate species-level identification for 98% (65/66) of monomicrobial and 88% (14/16) of polymicrobial BCs, with a TAT as short as ∼2·6 h. Accurate resistome profiling (allelic variants) was achieved for 94% (58/62) of the most clinically-relevant resistance profiles in ∼4·2 h. In silico serotying (Neisseria meningitidis), virulotyping (Escherichia coli, Klebsiella pneumoniae) and comparative phylogenomics for outbreak investigation (K. pneumoniae) proved also feasible.</p><p><strong>Interpretation: </strong>In this proof-of-concept study, we proved that diagnosis of BSI can be significantly shortened using an optimised workflow based on real-time sequencing, providing rapid, actionable clinical microbiological data in support of timely selection of appropriate chemotherapy. LC-WGS proved also useful as molecular epidemiology tool for public health and infection control applications.</p><p><strong>Funding: </strong>This study was partially supported by an investigator-initiated grant from Qvella Corporation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105633"},"PeriodicalIF":9.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656557","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":"The INO80E at 16p11.2 locus increases risk of schizophrenia in humans and induces schizophrenia-like phenotypes in mice.","authors":"Bo Hu, Mei-Yu Yin, Chu-Yi Zhang, Zhe Shi, Lu Wang, Xiaoming Lei, Ming Li, Shi-Wu Li, Qin-Hui Tuo","doi":"10.1016/j.ebiom.2025.105645","DOIUrl":"10.1016/j.ebiom.2025.105645","url":null,"abstract":"<p><strong>Background: </strong>Chromosome 16p11.2 is one of the most significant loci in the genome-wide association studies (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies having been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized.</p><p><strong>Methods: </strong>We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed a murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of adeno-associated virus (AAV), followed by behavioural assessments, dendritic spine analyses and RNA sequencing.</p><p><strong>Findings: </strong>We identified significant associations between elevated INO80E mRNA expression in the frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviours, including increased anxiety behaviour, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labelling assay showed that the density of stubby spines in the pyramidal neurons of mPFC was significantly increased in Ino80e-OE mice compared with control mice. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e.</p><p><strong>Interpretation: </strong>Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviours in mice, further supporting the hypothesis that INO80E is an authentic risk gene.</p><p><strong>Funding: </strong>This project received support from the National Key Research and Development Program of China, National Natural Science Foundation of China, Key Research and Development Projects of Hunan Provincial Science and Technology Department, Science and Technology Innovation team of Hunan Province, etc.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105645"},"PeriodicalIF":9.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633523","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":"VIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4.","authors":"Yuening Jiang, Jie Li, Tianzhen Wang, Xiaoyang Gu, Xinyu Li, Zhaofei Liu, Wei Yue, Mo Li","doi":"10.1016/j.ebiom.2025.105646","DOIUrl":"10.1016/j.ebiom.2025.105646","url":null,"abstract":"<p><strong>Background: </strong>The high mortality rate associated with epithelial ovarian cancer (EOC) is primarily due to recurrence and chemoresistance, underscoring the urgent need for innovative therapeutic approaches that leverage newly identified vulnerabilities in cancer cells. While conventional chemotherapies induce apoptosis by targeting DNA or mitotic machinery, ferroptosis represents a new distinct form of programmed cell death characterised by the accumulation of lipid peroxides.</p><p><strong>Methods: </strong>The sensitivity of different EOC cell lines to ferroptosis inducers was evaluated using cell viability assays and lipid peroxidation measurements. Live-cell imaging with the pH-sensitive CD63-pHuji reporter was performed to track the extracellular export of acyl-CoA synthetase long-chain family member 4 (ACSL4) via exosomes. The upstream regulator of ACSL4 were identified through immunoprecipitation-mass spectrometry (IP-MS) and validated using protein binding assays. Finally, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were utilised to evaluate the therapeutic potential overcoming ferroptosis resistance.</p><p><strong>Findings: </strong>In this study, we found that interferon (IFN)-γ combined with arachidonic acid (AA), which are endogenous ferroptosis inducers, could initiate ferroptosis in most EOC cells. However, some EOC cells displayed significant resistance. Contrary to the typical increase in ACSL4 protein observed in ferroptosis-sensitive cells, resistant EOC cells exhibited surprisingly low levels of this pro-ferroptotic lipid metabolic protein. Intriguingly, this reduction is attributed to the exosomal expulsion of ACSL4 protein, revealing a distinct cellular mechanism to evade ferroptosis. We further identified VIPAS39 as a pivotal regulator in sorting ACSL4 into late endosomes, thereby facilitating their subsequent release as exosomes. Notably, targeting VIPAS39 not only overcomes the resistance to ferroptotic cell death but also markedly suppresses tumour growth.</p><p><strong>Interpretation: </strong>Our findings uncover the crucial role of VIPAS39 in ferroptosis evasion by facilitating the exporting of ACSL4 protein via exosomes, highlighting VIPAS39 as a promising target for ferroptosis-based anti-cancer therapy.</p><p><strong>Funding: </strong>Funded by Beijing Municipal Natural Science Foundation (Key program Z220011), National Natural Science Foundation of China (NSFC) (T2225006, T2488301, 82272948), Peking University Medicine Youth Science and Technology Innovation 'Sail Plan' Project Type B Medical Interdisciplinary Seed Fund (71006Y3171), GuangDong Basic and Applied Basic Research Foundation (2021A1515110820), and the special fund of the National Clinical Key Speciality Construction Program, P. R. China (2023).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105646"},"PeriodicalIF":9.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633538","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}