Targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease  

作　　者：Jie Tong Dongjie Li Hongbo Meng Diyang Sun Xiuting Lan Min Ni Jiawei Ma Feiyan Zeng Sijia Sun Jiangtao Fu Guoqiang Li Qingxin Ji Guoyan Zhang Qirui Shen Yuanyuan Wang Jiahui Zhu Yi Zhao Xujie Wang Yi Liu Shenxi Ouyang Chunquan Sheng Fuming Shen Pei Wang 

机构地区：[1]Department of Pharmacy,Shanghai Tenth People’s Hospital,Tongji University School of Medicine,Shanghai 200072,China [2]Department of Pharmacology,School of Pharmacy,Naval Medical University/Second Military Medical University,Shanghai 200433,China [3]Department of General Surgery,Shanghai Tenth People’s Hospital,Tongji University School of Medicine,Shanghai 200072,China [4]Department of Pharmacy,Shanghai Fourth People’s Hospital,Tongji University School of Medicine,Shanghai 200081,China [5]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China [6]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325000,China [7]Department of Medicinal Chemistry,School of Pharmacy,Naval Medical University/Second Military Medical University,Shanghai 200433,China [8]Institute of Nuclear Medicine,Tongji University School of Medicine,Shanghai 200072,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第9期3650-3666,共17页药学学报（英文版）

基　　金：supported by the grants from National Natural Science Foundation of China (82073915, 91849135, 81673485, 81773719, 81973312 and 81971306);National Key Research and Development Project (2018YFA0108301, China);Shanghai Science and Technology Commission Experimental Animal Grants (21XD1424900, 19140904700, 19140904900 and 21S11901200, China);Shanghai Shuguang Program (19SG32, China);Shanghai “Rising Stars of Medical Talent” Youth Development ProgramYouth Medical Talents-Clinical Pharmacist Program [SHWRS(2020)_087, China]

摘　　要：Metabolic-associated fatty liver disease(MAFLD),which is previously known as non-alcoholic fatty liver disease(NAFLD),represents a major health concern worldwide with limited therapy.Here,we provide evidence that ferroptosis,a novel form of regulated cell death characterized by iron-driven lipid peroxidation,was comprehensively activated in liver tissues from MAFLD patients.The canonical-GPX4(cGPX4),which is the most important negative controller of ferroptosis,is downregulated at protein but not mRNA level.Interestingly,a non-canonical GPX4 transcript-variant is induced(inducible-GPX4,iGPX4)in MAFLD condition.The high fat-fructose/sucrose diet(HFFD)and methionine/choline-deficient diet(MCD)-induced MAFLD pathologies,including hepatocellular ballooning,steatohepatitis andfibrosis,were attenuated and aggravated,respectively,in cGPX4-and iGPX4-knockin mice.cGPX4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in hepatocytes.Knockdown of iGPX4 by siRNA alleviated lipid stress,ferroptosis and cell injury.Mechanistically,the triggered iGPX4 interacts with cGPX4 to facilitate the transformation of cGPX4 from enzymatic-active monomer to enzymatic-inactive oligomers upon lipid stress,and thus promotes ferroptosis.Co-immunoprecipitation and nano LC–MS/MS analyses confirmed the interaction between iGPX4 and cGPX4.Our results reveal a detrimental role of non-canonical GPX4 isoform in ferroptosis,and indicate selectively targeting iGPX4 may be a promising therapeutic strategy for MAFLD.

关 键 词：Ferroptosis GPX4 Alternative isoform Fatty liver OLIGOMERIZATION Methionine/choline-deficient diet High fat-fructose/sucrose diet Protein interaction 

分 类 号：R575.5[医药卫生—消化系统]