The cGAS-STING pathway promotes hepatic fibrosis in type 2 diabetes-associated MASLD by enhancing the glycolysis-lactate axis in hepatic stellate cells

Type 2 diabetes mellitus (T2DM) is a major risk factor for fibrosis progression in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) is a key regulator of immune and metabolic pathways, and has been implicated in liver fibrogenesis. This study aims to elucidate the role of the cGAS-STING pathway in T2DM-associated MASLD fibrosis and its underlying mechanisms. A T2DMmouse model was established in male C57BL/6J mice by a high-fat diet (HFD) with a low-dose intraperitoneal streptozotocin (STZ) injection, followed by assessment of hepatic biochemical parameters. For the in vitro model, mouse hepatic stellate cells (mHSCs) were treated with high glucose and palmitic acid (HGPA) to mimic the glucolipotoxic microenvironment of T2DM. The cGAS-STING pathway was markedly activated in the liver of T2DM conditions. Pharmacologic inhibition of STING with C176 attenuated liver fibrosis in vivo and suppressed HSC activation in vitro. Mechanistically, cGAS-STING inhibition reduced the expression of key glycolytic enzymes, decreased intracellular pyruvate and lactate accumulation, and downregulated the fibrotic markers αSMA and COL1A1. Moreover, exogenous sodium lactate partially reversed the inhibitory effect of C176 on HSC activation, supporting a role for the glycolysis-lactate axis downstream of cGAS-STING signaling. These findings suggest that the cGAS-STING pathway promotes HSC activation and liver fibrosis in T2DM-associated MASLD, at least in part by enhancing glycolytic reprogramming and lactate production. Targeting the cGAS-STING-lactate axis may therefore represent a potential therapeutic strategy for fibrosis in the setting of T2DM-associated MASLD.