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

引用

Acta Pharmaceutica Sinica B 2022年第9期12卷 3650-3666页

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 Department of Pharmacy Shanghai Tenth People’s HospitalTongji University School of MedicineShanghai 200072China Department of Pharmacology School of PharmacyNaval Medical University/Second Military Medical UniversityShanghai 200433China Department of General Surgery Shanghai Tenth People’s HospitalTongji University School of MedicineShanghai 200072China Department of Pharmacy Shanghai Fourth People’s HospitalTongji University School of MedicineShanghai 200081China Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Chemical Biology Research Center School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325000China Department of Medicinal Chemistry School of PharmacyNaval Medical University/Second Military Medical UniversityShanghai 200433China Institute of Nuclear Medicine Tongji University School of MedicineShanghai 200072China

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.

关键词： Ferroptosis GPX4 alternative isoform Fatty liver Oligomerization Methionine/choline-deficient diet High fat-fructose/sucrose diet Protein interaction

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