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 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

作者机构：Department of PharmacyShanghai Tenth People’s HospitalTongji University School of MedicineShanghai 200072China Department of PharmacologySchool of PharmacyNaval Medical University/Second Military Medical UniversityShanghai 200433China Department of General SurgeryShanghai Tenth People’s HospitalTongji University School of MedicineShanghai 200072China Department of PharmacyShanghai Fourth People’s HospitalTongji University School of MedicineShanghai 200081China Shanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Chemical Biology Research CenterSchool of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325000China Department of Medicinal ChemistrySchool of PharmacyNaval Medical University/Second Military Medical UniversityShanghai 200433China Institute of Nuclear MedicineTongji University School of MedicineShanghai 200072China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第9期

页      面：3650-3666页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

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] 

主　　题：Ferroptosis GPX4 Alternative isoform Fatty liver Oligomerization Methionine/choline-deficient diet High fat-fructose/sucrose diet Protein interaction 

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 ***,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 *** canonical-GPX4(cGPX4),which is the most important negative controller of ferroptosis,is downregulated at protein but not mRNA ***,a non-canonical GPX4 transcript-variant is induced(inducible-GPX4,iGPX4)in MAFLD *** 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 ***4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in *** of iGPX4 by siRNA alleviated lipid stress,ferroptosis and cell ***,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 ***-immunoprecipitation and nano LC–MS/MS analyses confirmed the interaction between iGPX4 and *** 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.