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Accumulating evidence indicates that, rather than operating as independent processes, immune activation, metabolic reprogramming, and cellular senescence are closely interconnected during fibrogenesis, jointly driving hepatic stellate cell (HSC) activation, ductular reaction, and excessive extracellular matrix deposition. In this review, we synthesize current understanding of how innate and adaptive immune responses, metabolic remodeling in hepatocytes and HSCs, and senescent cells with their senescence-associated secretory phenotype cooperatively sustain fibrotic progression, with particular emphasis on bidirectional and context-dependent cross-talk. We further highlight key regulatory nodes\u2014including NF-\u03baB, AMPK-mTOR, SIRT1\/3, the NLRP3 inflammasome, and the YAP\/TAZ pathway\u2014that integrate signals across these interconnected pathways. Recent advances in multi-omics profiling, spatial transcriptomics, and organoid-based models have provided new opportunities to interrogate this integrated network at cellular and spatial resolution. From a translational perspective, therapeutic strategies targeting immunometabolic regulation, inflammasome activation, and cellular senescence, especially when combined with cell-type-specific intervention approaches, may offer promising avenues for restoring tissue homeostasis and reversing liver fibrosis.<\/jats:p>","DOI":"10.1042\/cs20261837","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:41:09Z","timestamp":1790239269000},"page":"2089-2105","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunity-metabolism-senescence axis in liver fibrosis: mechanistic insights, therapeutic targets, and translational opportunities"],"prefix":"10.1042","volume":"140","author":[{"given":"Yaxuan","family":"Cao","sequence":"first","affiliation":[{"name":"1Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2354-230X","authenticated-orcid":false,"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"},{"name":"2Precision Regenerative Medicine Research Centre, Medical Science Division, Macau University of Science and Technology, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6231-3035","authenticated-orcid":false,"given":"Kwong\u00a0Hang\u00a0Paul","family":"Tam","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"},{"name":"2Precision Regenerative Medicine Research Centre, Medical Science Division, Macau University of Science and Technology, Macao 999078, China"},{"name":"3School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"2026092404410183700_B1","doi-asserted-by":"publisher","first-page":"7260","DOI":"10.3748\/wjg.v20.i23.7260","article-title":"Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update","volume":"20","author":"Elpek","year":"2014","journal-title":"World J. 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