GSTM1 suppresses cardiac fibrosis post-myocardial infarction through inhibiting lipid peroxidation and ferroptosis

作者：Kai‐Jie Chen, Yue Zhang, Xin-Yi Zhu, Shuo Yu, Yao Xie, Chong Wei Jin, Yimin Shen, Siyu Zhou, Xiao-Ce Dai, Sheng-an Su, Lan Xie, Zheng-Xing Huang, Hui Gong, Mei-Xiang Xiang, Hong Ma · 发表于：Military Medical Research · 年份：2025 · DOI：10.1186/s40779-025-00610-6 · 被引用次数：12 · 研究领域：Cardiac Fibrosis and Remodeling、Glutathione Transferases and Polymorphisms、Protease and Inhibitor Mechanisms

BACKGROUND: Cardiac fibrosis following myocardial infarction (MI) drives adverse ventricular remodeling and heart failure, with cardiac fibroblasts (CFs) playing a central role. GSTM1 is an important member of the glutathione S-transferase (GSTs) family, which plays an important role in maintaining cell homeostasis and detoxification. This study investigated the role and mechanism of GSTM1 in post-MI fibrosis. METHODS: Multi-omics approaches (proteomics/scRNA-seq) identified GSTM1 as a dysregulated target in post-MI fibroblasts. Using a murine coronary ligation model, we assessed GSTM1 dynamics via molecular profiling, such as Western blotting, immunofluorescence, and real-time quantitative polymerase chain reaction. AAV9-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery. In vitro studies employed transforming growth factor-β (TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions. Mechanistic insights were derived from transcriptomics and lipid peroxidation assays. RESULTS: The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels. In human dilated cardiomyopathy (DCM) patients with severe heart failure, GSTM1 expression was decreased alongside aggravated fibrosis. Overexpression of GSTM1 in post-MI mice improved cardiac function, while significantly reducing infarct size and fibrosis compared with the control group. In vitro models demonstrated that GSTM1 mark...