Context-dependent STAT3 signaling in liver fibrosis.

Abstract

Liver fibrosis is a central pathological process driving the progression of chronic liver disease to cirrhosis and involves complex signaling networks across multiple cell types. Signal transducer and activator of transcription 3 (STAT3) serves as a signaling hub that integrates inflammatory, metabolic, and fibrogenic signals and exerts pleiotropic regulatory functions in liver fibrosis. STAT3 structure and subcellular localization provide the scaffold for signal encoding, whereas post-translational modifications (PTMs) alter STAT3 stability, dimerization, localization, transcriptional activity, and protein interactions. These regulatory states are further translated through direct transcriptional control, epigenetic mechanisms, non-coding RNA networks, signaling crosstalk, metabolic reprogramming, and oxidative stress into cell-specific phenotypes within the fibrotic microenvironment. Current evidence most consistently supports a pro-fibrotic role for STAT3 activation in HSC-centered fibrogenic programs, whereas several PTM-dependent, metabolic, and cell-protective mechanisms remain context-restricted or incompletely validated. Herein, we provide a structured narrative synthesis of STAT3 regulation in liver fibrosis, dissect the current status and challenges of targeted therapeutic strategies, and discuss how context-matched STAT3 modulation may inform future anti-fibrotic strategies.