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

• DOI: 10.1016/j.apsb.2022.02.003
• Publication Date: 2022-02-12T07:44:11Z
• Authors: 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
• Keywords: GPX4; Steatohepatitis

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