Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
FASEB J. 2022 Jul;36(7):e22399. doi: 10.1096/fj.202200241RR.
Acute kidney injury (AKI) is a common clinical problem and an efficacious treatment is lacking. Ferroptosis, a newly discovered type of programmed cell death, has been reported to alleviate renal tubular injury in ischemia/reperfusion-induced acute kidney injury (I/R-AKI). Entacapone is a specific inhibitor of catechol-O-methyltransferase, which is used as an adjuvant drug against Parkinson's disease. We demonstrated that entacapone prevents renal I/R injury by inhibiting ferroptosis. Compared with a sham group, entacapone treatment mitigated I/R-induced pathological alterations, improved renal function, and inhibited ferroptosis. In HK-2 cells, entacapone treatment significantly reduced the lipid peroxidation and iron accumulation induced by the ferroptosis inducers erastin and RSL3, and significantly regulated expression of ferroptosis-related proteins. Entacapone upregulates p62 expression and affects the p62-KEAP1-NRF2 pathway, thereby upregulating nuclear translocation of NRF2. This action results in increased expression of the downstream SLC7A11, and significant suppression of oxidative stress and ferroptosis. Our results identify entacapone as a ferroptosis inhibitor that enhances antioxidant capacity. Entacapone may serve as a novel strategy to improve treatment of, and recovery from, I/R-AKI.
急性肾损伤（AKI）是一种常见的临床问题，目前缺乏有效的治疗方法。铁死亡是一种新发现的程序性细胞死亡方式，有研究报道其可减轻缺血/再灌注诱导的急性肾损伤（I/R-AKI）中的肾小管损伤。恩他卡朋是儿茶酚-O-甲基转移酶的特异性抑制剂，被用作治疗帕金森病的辅助药物。我们证明，恩他卡朋通过抑制铁死亡来预防肾 I/R 损伤。与假手术组相比，恩他卡朋治疗减轻了 I/R 引起的病理改变，改善了肾功能，并抑制了铁死亡。在 HK-2 细胞中，恩他卡朋处理显著减少了铁死亡诱导剂 erastin 和 RSL3 引起的脂质过氧化和铁积累，并显著调节了铁死亡相关蛋白的表达。恩他卡朋上调了 p62 的表达并影响了 p62-KEAP1-NRF2 通路，从而促进了 NRF2 的核转位。这一作用导致下游 SLC7A11 的表达增加，显著抑制了氧化应激和铁死亡。我们的结果表明，恩他卡朋是一种增强抗氧化能力的铁死亡抑制剂。恩他卡朋可能成为改善 I/R-AKI 治疗和恢复的新策略。
