Vincamine attenuates alcoholic liver injury through modulation of a CDK1-glycolysis-NLRP3 immunometabolic axis

Alcoholic liver disease (ALD) is the major immunometabolic disorder characterized by dysregulated lipid metabolism and persistent activation of hepatic innate immune responses. Vincamine (Vin), isolated from Vinca minor, has been reported to exhibit diverse pharmacological activities. Nevertheless, the immunomodulatory effects and underlying mechanisms of Vin on ALD remain poorly understood.

This study aimed to explore the protective effects of Vin against alcohol-induced hepatic injury, with a particular focus on immunometabolic regulation of inflammasome activation.

An acute ethanol-fed mouse model was established using male C57BL/6 mice. In vitro experiments were performed using ethanol-stimulated AML12 and HepG2 hepatocytes, as well as LPS/ATP-activated murine peritoneal macrophages.

Vin significantly attenuated hepatic steatosis in ethanol-fed mice through modulation of lipid metabolism-associated genes, notably SREBP1 and PPARα. Vin also modulated glycolysis-related pathways through regulation of CDK1, GLUT1, and HIF-1α. In vivo, Vin markedly reduced alcohol-induced immune cell infiltration and suppressed activation of the TLR4-NLRP3 inflammasome pathway. In hepatocytes, Vin alleviated ethanol-induced lipid accumulation, accompanied by downregulation of CDK1 and GLUT1 and reduced NLRP3 activation and IL-1β secretion. In macrophages, Vin inhibited LPS/ATP-induced IL-1β and Caspase-1 expression. Mechanistically, CDK1 deficiency impaired glycolytic activity, as reflected by reduced expression of GLUT1, HIF-1α, and LDHA, and subsequently alleviated lipid accumulation and inflammatory responses under ethanol exposure.

Vin exerts protective effects against alcohol-induced hepatic steatosis and inflammation by modulating a CDK1-associated metabolic-inflammatory axis involving glycolysis and NLRP3 inflammasome activation.