{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:06:42Z","timestamp":1784696802602,"version":"3.55.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Alcohol-related liver disease (ALD) is a major cause of liver-related morbidity and mortality worldwide, yet the associations linking alcohol-induced gut microbial alterations to metabolic remodeling and hepatocyte dysfunction remain incompletely understood. Here, we applied an integrative multi-omics strategy combining untargeted fecal metabolomics, shotgun metagenomics, mouse liver bulk RNA sequencing, and reanalysis of publicly available human hepatic single-cell and bulk transcriptomic datasets to characterize alcohol exposure-associated gut\u2013liver immunometabolic features. In a mouse model of acute ethanol-induced liver injury, fecal metabolomic and metagenomic profiling revealed marked alterations in microbial functional potential and fecal metabolic composition, identifying six convergent metabolic pathways across fecal multi-omics layers, including nucleotide metabolism, the pentose phosphate pathway, histidine metabolism, glycerophospholipid metabolism, glycine\/serine\/threonine metabolism, and the phosphotransferase system. Reanalysis of human ALD single-cell transcriptomes showed hepatocyte-enriched activity patterns for several corresponding pathways, suggesting potential pathway-level associations between fecal metabolic alterations and hepatic transcriptional responses. Integrative transcriptomic analysis further identified a ten-gene hepatocyte-associated signature, comprising LRG1, ORM1, ORM2, TAT, HP, FGB, FGG, ITIH3, NNMT, and AGT, which was associated with pathway activity and showed consistent upregulation across acute ethanol-induced liver injury and human ALD\/AH transcriptomic datasets. In an external human cohort, this signature stratified patients into exploratory molecular subgroups with distinct metabolic pathway activities and clinical outcome distributions. Collectively, these findings provide a hypothesis-generating multi-omics framework for investigating alcohol-related liver injury and support further validation in chronic ethanol exposure models and functional studies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1844110","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:46:49Z","timestamp":1784695609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics analysis identifies a hepatocyte-associated signature in alcohol-related liver injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Ran","family":"Ding","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus","place":["Guangzhou, China"]},{"name":"National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of 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