Deubiquitinase OTUD7B stabilizes HNF4α to alleviate pressure overload-induced cardiac hypertrophy by regulating fatty acid oxidation and inhibiting ferroptosis

作者：R Q Zheng, Wenjuan Song, Che Wang, Xiaoyu Du, Chunlei Liu, Xiaotong Sun, Chengzhi Lu · 发表于：Biomarker Research · 年份：2025 · DOI：10.1186/s40364-025-00766-2 · 被引用次数：8 · 研究领域：Ferroptosis and cancer prognosis、Immune cells in cancer、Cardiac Fibrosis and Remodeling

Abstract Background Cardiac hypertrophy, a leading cause of heart failure, threatens global public health. Deubiquitinating enzymes (DUBs) are critical in cardiac pathophysiology by regulating protein stability, function, and degradation. Here, we investigated the role and regulating mechanism of ovarian tumor domain-containing 7B (OTUD7B) in cardiac hypertrophy by modulating fatty acid metabolism. Methods Mice subjected to transverse aortic constriction (TAC) and cardiomyocytes treated with phenylephrine (PE) were used to explore the role of OTUD7B in myocardial hypertrophy. The potential molecular mechanisms underlying OTUD7B's regulation of cardiac hypertrophy were explored through transcriptome analysis and further validated in cardiomyocytes. Results Reduced OTUD7B expression was observed in hypertrophic hearts following TAC surgery. Cardiac-specific OTUD7B deficiency exacerbated, while OTUD7B overexpression mitigated, pressure overload-induced hypertrophy and cardiac dysfunction both in vivo and in vitro. OTUD7B knockdown resulted in ferroptosis, as evidenced by decreased mitochondrial cristae, increased Fe 2+ ion content, lipid peroxide accumulation, while OTUD7B overexpression inhibited ferroptosis. Mechanistically, transcriptomic analysis identified OTUD7B plays a role in the regulation of fatty acid metabolism and pathological cardiac hypertrophy. OTUD7B was found to directly bind to HNF4α, a transcription factor regulating fatty acid oxidation-related genes. Furthe...