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The JAK\/STAT signaling pathway has emerged as a central regulator of cytokine signaling in the liver and is increasingly considered a potential therapeutic target. However, its biological effects are highly context-dependent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body<\/jats:title>\n                    <jats:p>In this review, we address a central question: is the JAK\/STAT pathway a practical therapeutic target in liver disease, or does its context-dependent biology limit direct clinical translation? We summarize how JAK\/STAT signaling regulates antiviral defense, immune tolerance, macrophage polarization, hepatic stellate cell activation, fibrogenesis, and tumor-promoting inflammation across viral hepatitis, autoimmune liver disease, NAFLD\/NASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Importantly, the evidence indicates that JAK\/STAT signaling is not uniformly pathogenic. Its effects vary according to disease stage, upstream cytokine milieu, canonical versus non-canonical activation, and, critically, cell type-specific responses in hepatocytes, immune cells, hepatic stellate cells, and tumor-associated cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This review examines the molecular mechanisms of this signaling pathway in various liver pathologies, summarizes the current research into regulating these signals as a potential treatment for chronic liver disease. Rather than broad pathway inhibition, future strategies should focus on cell-specific, disease-stage-specific, and function-selective modulation to suppress pathogenic inflammation and fibrosis while preserving antiviral immunity and tissue-repair programs. This framework may better support precision medicine approaches for chronic liver disease and liver cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08135-9","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T10:32:26Z","timestamp":1776249146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["JAK\/STAT signaling in liver disease: a therapeutic target or a context-dependent double-edged sword?"],"prefix":"10.1186","volume":"24","author":[{"given":"Tuokai","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanjuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"8135_CR1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","volume":"70","author":"SK Asrani","year":"2019","unstructured":"Asrani SK, Devarbhavi H, Eaton J, Kamath PS. 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