Suppression of PKM2 by Leonurine Attenuates Alcoholic Hepatitis Through Regulating Glycolytic Reprogramming

Alcoholic hepatitis (AH) is a liver disease caused by long-term heavy drinking. In the early stages, it usually manifests as fatty liver, which can then develop into liver fibrosis and cirrhosis. Kupffer cells are liver resident macrophages and the effect of glycolytic reprogramming on the polarization of macrophages plays an important role in hepatitis, which maybe a possibility therapeutic target for treating AH. Leonurine (Leo) is a natural alkaloid from Leonurus japonicus Houtt. and has been commonly used to ameliorate metabolic disorders. However, the protective effects and underlying mechanisms of Leo against alcoholic liver disease remain unclear. The study aimed to investigate the novel role of PKM2 on AH, and whether targeting PKM2-mediated glycolytic reprogramming is the underlying mechanism for the anti-inflammatory effects of Leo to regulate the AH. To investigate the potential role of Leo and its mechanisms on AH, we established an alcohol-induced C57BL/6 mice and LPS&IFN-γ-induced kupffer cell model to evaluate its pharmacological activity and mechanisms on AH in vivo and vitro. Our results showed that Leo treatment could restrain liver inflammation and inhibit PKM2 expression in vivo and in vitro, reducing the upregulated glycolysis. Additionally, treatment of Leo ameliorated extensive vacuolar degeneration and reduced lipid droplet accumulation in AH mice. The decrease of PKM2 expression apparently attenuated glycolysis and liver inflammation in vivo and in vitro. Leo interacted with PKM2 to modulate glycolysis for switching glycolytic reprogramming, thereby suppressing liver inflammation during AH. Our data highlighted that inhibition of PKM2 may be an effective strategy for treating AH. Leo possesses a beneficial amelioration effect on AH through inhibiting PKM2-mediated glycolytic reprogramming. These findings demonstrate an experimental basis for the clinical application of Leo in the treatment of AH.