Pharmacological inhibition of GLUT1 alleviates fulminant hepatitis by restraining macrophage-induced inflammatory cascades and restoring metabolic homeostasis

Fulminant hepatitis (FH) is a life-threatening clinical syndrome characterized by massive hepatocyte necrosis and rapid liver failure, with limited therapeutic options beyond transplantation. Although hepatic macrophages are known to drive FH immunopathology, the metabolic mechanisms governing their hyperactivation remain poorly understood. In this study, we investigated the role of glucose transporter 1 (GLUT1)-mediated metabolic reprogramming in the progression of D-gal/LPS-induced FH. GLUT1 is significantly upregulated in hepatic macrophage during acute injury, facilitating a shift toward aerobic glycolysis. This glycolytic surge, regulated via the PI3K/AKT signaling pathway, serves as a fundamental driver for pro-inflammatory M1 macrophage polarization and the subsequent cytokine storm. Notably, pharmacological inhibition of GLUT1 with WZB117 effectively suppressed glycolytic flux, attenuated M1-type activation, and restored lipid metabolic homeostasis, thereby significantly reducing hepatocellular apoptosis and systemic inflammation. Transcriptomic and metabolomic profiling confirmed that GLUT1 inhibition rebalances the immune microenvironment by intercepting the macrophage-mediated inflammatory cascade at its inception. Collectively, these findings identify GLUT1 as a pivotal molecular switch in macrophage-intrinsic metabolic reprogramming and suggest that targeting GLUT1-mediated glycolysis represents a promising therapeutic strategy for the clinical management of fulminant hepatic failure.