JAK/STAT signaling in liver disease: a therapeutic target or a context-dependent double-edged sword?

Liver disease remains a major global health burden, and effective targeted therapies are still lacking for many conditions, particularly chronic inflammatory, fibrotic, and malignant liver diseases. 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. 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. 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.