Hepatic Macrophage STING Signaling in Liver Fibrosis: Mechanisms and Therapeutic Perspectives.

Abstract

Liver fibrosis (LF) arises from chronic liver injury, in which a persistently pro-inflammatory microenvironment shaped by hepatic macrophages drives hepatic stellate cells (HSCs) activation and fibrosis progression. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway serves as a molecular hub linking metabolic liver injury to immune and inflammatory responses, sensing danger signals from metabolic stress, mitochondrial injury, and cell death to initiate downstream inflammatory transcription. This signaling may sustain a pro-inflammatory macrophage phenotype and amplify inflammation, potentially driving fibrosis from reversible repair toward progressive disease. This review summarizes the pathological mechanisms and translational advances of macrophage STING signaling in LF, discusses how STING integrates mitochondrial DNA (mtDNA) sensing with non-canonical metabolic stress signals to sustain pro-inflammatory macrophage states via bioenergetic and organelle remodeling, and evaluates emerging therapeutic strategies aimed at modulating macrophage STING signaling, including mesenchymal stem cell (MSC)/exosome-based approaches and natural-product interventions, for the potential therapeutic management of LF.