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

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

doi:10.1016/j.eng.2024.05.005

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工程（英文） ›› 2024, Vol. 41 ›› Issue (10) : 189-203. DOI: 10.1016/j.eng.2024.05.005

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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

曲桁东 ^a^,^b ,
张迪 ^a^,^b ,
刘均立 ^a^,^b ,
邓洁萍 ^c ,
谢若研 ^b ,
张珂珂 ^b ,
李红梅 ^b ,
陶萍 ^a^,^b ,
汪根树 ^d ,
孙健 ^e ,
罗钧洪 ^c ,
曲辰 ^a^,^b ,
叶文才 ^a ,
洪健 ^a^,^b^,^e

作者信息 +

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

Hengdong Qu ^a^,^b^,^# ,
Di Zhang ^a^,^b^,^# ,
Junli Liu ^a^,^b^,^# ,
Jieping Deng ^c^,^# ,
Ruoyan Xie ^b ,
Keke Zhang ^b ,
Hongmei Li ^b ,
Ping Tao ^a^,^b ,
Genshu Wang ^d ,
Jian Sun ^e ,
Oscar Junhong Luo ^c ,
Chen Qu ^a^,^b ,
Wencai Ye ^a^,^* ,
Jian Hong ^a^,^b^,^e^,^*

Author information +

History +

Abstract

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/FLLysM-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/CCl₄). 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.

Keywords

Pyruvate kinase M2 / Macrophages / Nonparenchymal cells / Heteroduplex oligonucleotide / Nonalcoholic steatohepatitis / Liver fibrosis

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曲桁东, 张迪, 刘均立. 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. Engineering. 2024, 41(10): 189-203 https://doi.org/10.1016/j.eng.2024.05.005

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