STING organelle stress sensing in the liver drives hepatocyte fate and remodeling

The liver is continually challenged by metabolic overload, oxidative injury, and sterile inflammation, yet the mechanisms that translate intracellular damage into coordinated tissue remodeling remain incompletely unified. This review advances a tissue-centric framework positioning STING as an organelle-stress checkpoint in hepatic biology rather than a pathway restricted to antiviral defense. In liver tissue, STING links intracellular damage to hepatocyte fate decisions and multicellular remodeling. These parenchymal outcomes propagate across the hepatic microenvironment by amplifying sterile inflammatory circuits and directing macrophage activation, stellate cell transdifferentiation, and extracellular matrix remodeling, thereby determining whether injury resolves or progresses toward chronic fibrosis. A central implication is that hepatic STING signaling is frequently dominated by non-canonical outputs, including NF-κB-skewed cytokine programs, autophagy and metabolic rewiring, and death/senescence pathways, rather than interferon-centric signaling alone. This perspective helps reconcile why STING can be protective in selected acute settings yet pathogenic during sustained organelle stress. We propose that signal duration, subcellular trafficking/localization, and cell-type context are the primary determinants of STING function, implying that therapeutic strategies should prioritize context-selective modulation and restoration of stress thresholds instead of indiscriminate pathway inhibition. As a brief translational perspective, computational integration of clinical trajectories, imaging, digital pathology, and molecular stress signatures may eventually help stratify STING-linked stress states, but such applications require mechanistic grounding and external validation.