Zheng Rujie, Song Wenjuan, Wang Che, Du Xiaoyu, Liu Chunlei, Sun Xiaotong, Lu Chengzhi
The First Central Clinical School, Tianjin Medical University, Tianjin, China.
School of Medicine, Nankai University, Tianjin, China.
Biomark Res. 2025 Mar 29;13(1):53. doi: 10.1186/s40364-025-00766-2.
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.
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.
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 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. Further, OTUD7B exerted deubiquitination activity to stabilize the HNF4α protein by removing K48-linked ubiquitin chains, thereby preventing its degradation via the proteasomal pathway and linking the HNF4α degradation and ferroptosis. Finally, ferroptosis inhibitors, ferrostatin-1, alleviated OTUD7B inhibition-induced ferroptosis, fatty acid metabolism suppression, and myocardial hypertrophy.
We confirmed that OTUD7B is involved in the regulation of ferroptosis in pressure overload-induced cardiac hypertrophy and highlighted that OTUD7B alleviates cardiac hypertrophy by regulating ferroptosis and fatty acid oxidation through deubiquitination and stabilization of HNF4α.
心脏肥大是心力衰竭的主要原因，威胁着全球公共卫生。去泛素化酶（DUBs）通过调节蛋白质的稳定性、功能和降解，在心脏病理生理学中起关键作用。在此，我们通过调节脂肪酸代谢，研究了含卵巢肿瘤结构域7B（OTUD7B）在心脏肥大中的作用及其调控机制。
采用经主动脉缩窄（TAC）处理的小鼠和用去甲肾上腺素（PE）处理的心肌细胞，探讨OTUD7B在心肌肥大中的作用。通过转录组分析探索OTUD7B调节心脏肥大的潜在分子机制，并在心肌细胞中进一步验证。
TAC手术后，在肥厚的心脏中观察到OTUD7B表达降低。心脏特异性OTUD7B缺陷加剧了压力超负荷诱导的肥大和心脏功能障碍，而OTUD7B过表达则减轻了体内外的上述情况。OTUD7B敲低导致铁死亡，表现为线粒体嵴减少、铁离子含量增加、脂质过氧化物积累，而OTUD7B过表达抑制铁死亡。机制上，转录组分析表明OTUD7B在脂肪酸代谢和病理性心脏肥大的调节中起作用。发现OTUD7B直接与肝细胞核因子4α（HNF4α）结合，HNF4α是一种调节脂肪酸氧化相关基因的转录因子。此外，OTUD7B发挥去泛素化活性，通过去除K48连接的泛素链来稳定HNF4α蛋白，从而防止其通过蛋白酶体途径降解，并将HNF4α降解与铁死亡联系起来。最后，铁死亡抑制剂铁抑素-1减轻了OTUD7B抑制诱导的铁死亡、脂肪酸代谢抑制和心肌肥大。
我们证实OTUD7B参与压力超负荷诱导的心脏肥大中铁死亡的调节，并强调OTUD7B通过去泛素化和稳定HNF4α来调节铁死亡和脂肪酸氧化，从而减轻心脏肥大。
