Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Department of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, 210009, China.
Redox Biol. 2020 Sep;36:101619. doi: 10.1016/j.redox.2020.101619. Epub 2020 Jun 24.
Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis.
铁死亡是一种新近发现的细胞程序性死亡形式，但它的调控机制尚不完全清楚。在本研究中，我们报道 BRD7-P53-SLC25A28 轴在调节肝星状细胞（HSCs）中的铁死亡中起着关键作用。在暴露于铁死亡诱导剂后，通过抑制泛素-蛋白酶体途径，显著增加了含溴结构域蛋白 7（BRD7）蛋白的表达。CRISPR/Cas9 介导的 BRD7 敲除赋予 HSC 对铁死亡的抗性，而特异性 BRD7 质粒介导的 BRD7 过表达促进了 HSC 铁死亡。有趣的是，升高的 BRD7 表达通过与 p53 N 端反式激活结构域（TAD）直接结合来促进 p53 线粒体易位，这可能是 BRD7 增强 HSC 铁死亡的潜在机制。丝氨酸 392 的定点突变完全阻断了 BRD7 与 p53 的结合，进而阻止了 p53 线粒体易位和 HSC 铁死亡。重要的是，线粒体 p53 与溶质载体家族 25 成员 28（SLC25A28）相互作用形成复合物，并增强了 SLC25A28 的活性，这可能导致氧化还原活性铁的异常积累和电子传递链（ETC）的过度功能。SLC25A28 的敲低削弱了 BRD7 或 p53 介导的铁死亡事件。在小鼠中，使用 erastin 治疗通过诱导 HSC 铁死亡来改善肝纤维化的病理损伤。HSC 特异性阻断 BRD7-P53-SLC25A28 轴可以阻断 erastin 诱导的 HSC 铁死亡。值得注意的是，我们分析了索拉非尼对接受索拉非尼单药治疗的晚期肝纤维化伴肝细胞癌患者 HSC 铁死亡的影响。有吸引力的是，在原代人 HSCs 中发生了 BRD7 上调、p53 线粒体易位、SLC25A28 与 p53 的结合以及铁死亡诱导。总的来说，这些发现揭示了铁死亡的新信号转导和调控机制，并表明 BRD7-P53-SLC25A28 轴可能成为肝纤维化的潜在靶点。
