https://doi.org/10.1016/j.apsb.2022.02.003
This new article publication from Acta Pharmaceutica Sinica B, discusses targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease.
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. The authors of this article 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.
These 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.
Article reference: 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, Targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease, Acta Pharmaceutica Sinica B, Volume 12, Issue 9, 2022, Pages 3650-3666, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2022.02.003.
Keywords: Ferroptosis, GPX4, Alternative isoform, Fatty liver, Oligomerization, Methionine/choline-deficient diet, High fat-fructose/sucrose diet, Protein interaction
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383522000533-ga1_lrg.jpg
Lipid stress induces iGPX4, which interacts with cGPX4 and facilitates the transformation of cGPX4 from monomer (active) to oligomers (inactive). The isoform iGPX4 promotes ferroptosis and deteriorate metabolic-associated fatty liver disease.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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CiteScore: 15.9
Impact Factor: 14.903
JIF without self-citation: 13.888
ISSN 2211-3835
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