1. Academic Validation
  2. GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

  • Front Cardiovasc Med. 2022 Jun 2;9:907747. doi: 10.3389/fcvm.2022.907747.
Kai Xu 1 Xiang Liu 2 Bin Wen 1 Yazhou Liu 1 Wei Zhang 1 Xiaolin Hu 3 Ling Chen 3 Weijian Hang 4 1 5 Juan Chen 1 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China.
  • 3 Neonatal Intensive Care Unit, Department of Pediatric, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
Abstract

Changes in modern lifestyle provoke a series of metabolic stresses such as hyperlipidemia. Excessive free fatty acids induce cardiomyocyte metabolic reprogramming and rearrangement of the lipid content of cardiomyocyte and promote oxidative stress. As a newly defined lipid peroxidation-related cell death pathway, the role of Ferroptosis in metabolic stress-induced cardiomyocyte injury is poorly revealed. Our work indicates that GSK-J4, a histone lysine demethylase 6A/6B dual inhibitor, can alleviate palmitic acid (PA)-induced hypersensitivity to Ferroptosis by suppressing H3K27 demethylation. Mechanistically, PA stimulation reduces the H3K27me3 level and hence promotes the expression of ACSL4, a key lipid modulator of Ferroptosis. GSK-J4 pretreatment significantly preserves the H3K27me3 level and reduces the ACSL4 level. GSK-J4 also reduces Reactive Oxygen Species to alleviate oxidative stress, which further decreases lipid peroxidation. Taken together, our data suggest that cardiomyocyte undergoes epigenetic reprogramming under metabolic challenges, rearranging lipid content, and sensitizing to Ferroptosis. GSK-J4 can be a potential drug for treating hyperlipidemia-induced cardiomyocyte injury by targeting epigenetic modulations.

Keywords

GSK-J4; H3K27me3; diabetic cardiomyocyte injury; epigenetic; ferroptosis; lipotoxicity.

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