Glycolysis drives STING signaling to promote M1-macrophage polarization and aggravate liver fibrosis.

Glycolysis activation plays a critical role in sustaining the proinflammatory phenotype of macrophages, which is key to initiating and advancing liver fibrosis. However, the underlying mechanisms that trigger glycolytic activation and their contribution to inflammation remain poorly understood. In this study, we showed that inhibiting glycolysis markedly suppresses macrophage M1 polarization and alleviates liver inflammation and fibrosis, whereas enhancing glycolysis in hepatic macrophages produces the opposite effect. Additionally, our results demonstrated that glycolytic flux is necessary for activation of the STING/TBK1/IRF3 pathway. Moreover, STING activation was found to reciprocally stimulate glycolysis in macrophages. Mechanistically, we found that ATP generated through glycolysis promotes STING pathway activation and enhances the interferon-dependent immune response. Moreover, activation of IRF3, a downstream transcription factor of STING, upregulates HIF-1α transcription, further driving glycolysis. These findings uncover novel mechanistic links between STING signaling and glycolytic metabolism, emphasizing their coordinated role in promoting macrophage M1 polarization. Together, our data suggest that targeting the interaction between metabolic reprogramming and immune signaling offers an effective therapeutic approach for treating liver fibrosis and cirrhosis.