Therapeutic Targeting of PKM2 Ameliorates NASH Fibrosis Progression in a Macrophage-Specific and Liver-Specific Manner  

靶向PKM2可有效改善非酒精性脂肪性肝炎及其相关肝纤维化进展

作　　者：Hengdong Qu Di Zhang Junli Liu Jieping Deng Ruoyan Xie Keke Zhang Hongmei Li Ping Tao Genshu Wang Jian Sun Oscar Junhong Luo Chen Qu Wencai Ye Jian Hong 曲桁东;张迪;刘均立;邓洁萍;谢若研;张珂珂;李红梅;陶萍;汪根树;孙健;罗钧洪;曲辰;叶文才;洪健

机构地区：[1]State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou 510632,China [2]Department of Pathophysiology,School of Medicine,Jinan University,Guangzhou 510632,China [3]Department of Microbiology and Immunology,School of Medicine,Jinan University,Guangzhou 510632,China [4]Department of Liver Transplantation,Guangdong Provincial Hospital of Traditional Chinese Medicine,Guangzhou 510630,China [5]Department of Hepatobiliary and Pancreatic Surgery,The First Affiliated Hospital of Jinan University,Guangzhou 510630,China

出　　处：《Engineering》2024年第10期189-203,共15页工程（英文）

基　　金：supported by the Key-Area Research and Development Program of Guangdong Province(2020B1111110004);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036);the Guangdong Major Project of Basic and Applied Basic Research(2023B0303000004);the National Natural Science Foundation of China(81871987,82293680,82293681,and 82273154);the Guangdong Basic and Applied Research Foundation(2023A1515012905 and 2022A1515012581)。

摘　　要：Nonalcoholic steatohepatitis(NASH)may soon become the leading cause of end-stage liver disease worldwide with limited treatment options.Liver fibrosis,which is driven by chronic inflammation and hepatic stellate cell(HSC)activation,critically determines morbidity and mortality in patients with NASH.Pyruvate kinase M2(PKM2)is involved in immune activation and inflammatory liver diseases;however,its role and therapeutic potential in NASH-related fibrosis remain largely unexplored.Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells(NPCs),especially macrophages,in the livers of patients with fibrotic NASH.Macrophage-specific PKM2 knockout(PKM2^(FL/FL)LysM-Cre)significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine-and choline-deficient(MCD)diet,a high-fat high-cholesterol(HFHC)diet,and a western diet plus weekly carbon tetrachloride injection(WD/CCl_(4)).Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6C^(high) macrophage infiltration.Mechanistically,PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3(NLRP3)activation in proinflammatory macrophages,which induced HSC activation and fibrogenesis.A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo.Translationally,ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides,a novel oligonucleotide drug that preferentially accumulates in the liver,dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity.The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis.Thus,therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

关 键 词：Pyruvate kinase M2 MACROPHAGES Nonparenchymal cells Heteroduplex oligonucleotide Nonalcoholic steatohepatitis Liver fibrosis 

分 类 号：R575.5[医药卫生—消化系统] R575.2[医药卫生—内科学]