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

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

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

Author: Jie TONG ¹ ; Dongjie LI ¹ ; Hongbo MENG ² ; Diyang SUN ³ ; Xiuting LAN ¹ ; Min NI ¹ ; Jiawei MA ¹ ; Feiyan ZENG ¹ ; Sijia SUN ¹ ; Jiangtao FU ³ ; Guoqiang LI ³ ; Qingxin JI ¹ ; Guoyan ZHANG ¹ ; Qirui SHEN ⁴ ; Yuanyuan WANG ¹ ; Jiahui ZHU ¹ ; Yi ZHAO ¹ ; Xujie WANG ¹ ; Yi LIU ¹ ; Shenxi OUYANG ¹ ; Chunquan SHENG ⁵ ; Fuming SHEN ¹ ; Pei WANG ³
Author Information

1. Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
2. Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
3. Department of Pharmacology, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China.
4. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, China.
5. Department of Medicinal Chemistry, School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai 200433, China.
Publication Type:Journal Article
Keywords: Alternative isoform; Fatty liver; Ferroptosis; GPX4; High fat-fructose/sucrose diet; Methionine/choline-deficient diet; Oligomerization; Protein interaction
From: Acta Pharmaceutica Sinica B 2022;12(9):3650-3666
CountryChina
Language:English
Abstract: 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 and ﬁbrosis, 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.