Macrophage PKM2 depletion ameliorates hepatic inflammation and acute liver injury in mice

Ziwei Kang¹Zhiwei Chen²Jincheng Li³Ruoyan Xie¹Jinyu Lv¹Weijia Ye³Yiming Cui¹Peixin Zhao¹Keke Zhang^1*Jian Hong^4*Hengdong Qu^4*

• ¹Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong Province, China
• ²Department of Hepatobiliary Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
• ³Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
• ⁴State Key Laboratory of Bioactive Molecules and Draggability Assessment, Jinan University, Guangzhou, China

Pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, plays a critical role in macrophage activation and a broad spectrum of chronic liver diseases. However, whether PKM2 contributes to the pathogenesis of acute liver injury (ALI) remains largely unexplored. By bioinformatic screening and analysis of ALI liver, we found that PKM2 was significantly upregulated in the liver tissues of ALI patients and mice.Immunofluorescence staining further demonstrated that PKM2 was markedly upregulated in macrophages during ALI progression. Notably, macrophage PKM2 depletion effectively alleviated acetaminophen (APAP)-and lipopolysaccharide/Dgalactosamine (LPS/D-GalN)-induced ALI, as demonstrated by ameliorated immune cells infiltration, pro-inflammatory mediators, and hepatocellular cell death. PKM2deficient macrophages showed M2 anti-inflammatory polarization in vivo and in vitro.Furthermore, PKM2 deletion limited HIF-1α signaling and aerobic glycolysis of macrophages, which thereby attenuated macrophage pro-inflammatory activation and hepatocyte injury. Pharmacological PKM2 antagonist efficiently ameliorated liver injury and prolonged the survival of mice in APAP-induced ALI model. Our study highlights the pivotal role of macrophage PKM2 in advancing ALI, and therapeutic targeting of PKM2 may serve as a novel strategy to combat ALI.