{"title":"Multi-omics integration reveals YWHAE as a key mediator of ferroptosis in ARDS","authors":"Honghui Cui, Xia Huang","doi":"10.1007/s10142-025-01603-3","DOIUrl":null,"url":null,"abstract":"<div><p>Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe hypoxemia and high mortality. Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, has emerged as a critical mechanism in ARDS pathogenesis. However, the molecular regulators of ferroptosis in ARDS remain unclear. This study integrates multi-omics analysis and experimental validation to identify ferroptosis-related targets in ARDS. Bronchoalveolar lavage fluid (BALF) samples from ARDS patients and healthy controls were subjected to proteomics and metabolomics analysis. Transcriptomic data from the GSE243066 dataset and ferroptosis-related gene databases were integrated to identify key genes. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. An LPS-induced ARDS mouse model was established for experimental validation, including Western blotting, histopathology, and ferroptosis-related biochemical assays. Multi-omics analysis identified YWHAE as a ferroptosis-associated gene significantly upregulated in ARDS. Functional enrichment revealed key pathways, including ferroptosis, hypoxia-inducible factor-1 signaling, and oxidative stress responses. Proteomic and transcriptomic integration highlighted 51 overlapping differentially expressed genes, with YWHAE emerging as a central hub in the protein–protein interaction network. Metabolomics analysis further revealed glutathione and cysteine metabolism as critical pathways linked to ferroptosis. In the ARDS mouse model, ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated LPS-induced lung injury, reduced oxidative stress markers, and downregulated YWHAE expression. This study identifies YWHAE as a novel ferroptosis-related target in ARDS through multi-omics analysis and experimental validation. These findings provide new insights into the molecular mechanisms of ferroptosis in ARDS and highlight YWHAE as a potential therapeutic target for future interventions.</p><h3>Graphical abstract</h3>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div><p>Created with biorender.com</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Functional & Integrative Genomics","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10142-025-01603-3","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe hypoxemia and high mortality. Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, has emerged as a critical mechanism in ARDS pathogenesis. However, the molecular regulators of ferroptosis in ARDS remain unclear. This study integrates multi-omics analysis and experimental validation to identify ferroptosis-related targets in ARDS. Bronchoalveolar lavage fluid (BALF) samples from ARDS patients and healthy controls were subjected to proteomics and metabolomics analysis. Transcriptomic data from the GSE243066 dataset and ferroptosis-related gene databases were integrated to identify key genes. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. An LPS-induced ARDS mouse model was established for experimental validation, including Western blotting, histopathology, and ferroptosis-related biochemical assays. Multi-omics analysis identified YWHAE as a ferroptosis-associated gene significantly upregulated in ARDS. Functional enrichment revealed key pathways, including ferroptosis, hypoxia-inducible factor-1 signaling, and oxidative stress responses. Proteomic and transcriptomic integration highlighted 51 overlapping differentially expressed genes, with YWHAE emerging as a central hub in the protein–protein interaction network. Metabolomics analysis further revealed glutathione and cysteine metabolism as critical pathways linked to ferroptosis. In the ARDS mouse model, ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated LPS-induced lung injury, reduced oxidative stress markers, and downregulated YWHAE expression. This study identifies YWHAE as a novel ferroptosis-related target in ARDS through multi-omics analysis and experimental validation. These findings provide new insights into the molecular mechanisms of ferroptosis in ARDS and highlight YWHAE as a potential therapeutic target for future interventions.
期刊介绍:
Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?