Cisplatin, a first-line chemotherapeutic agent commonly used to treat various solid tumors, induce severe adverse effects, especially nephrotoxicity, which largely limits its clinical application. However, the currently used measures to prevent nephrotoxicity are not ideal owing to the mechanisms underlying cisplatin-induced nephrotoxicity are not comprehensively understood. Herein, we examined the effects of silibinin on cisplatin-induced nephrotoxicity and found that silibinin exerted cytoprotection effects during cisplatin treatment in HEK293 cells and in a cisplatin-induced acute kidney injury (AKI) model. Mechanistically, silibinin ameliorated cisplatin-induced AKI via decreasing ROS-mediated MAPK signaling pathway activation, which was confirmed using the inhibitor N-acetylcysteine. Moreover, the protective effect of silibinin against cisplatin-induced ROS generation through the antioxidant transcription factor nuclear factor-erythroid 2-related factor 1 (Nfe2l1), rather than Nfe2l2, mediates HO1 expression. Furthermore, interference with the abundance of Nfe2l1 using siRNA or an overexpression plasmid enhanced or decreased the effect of cisplatin-induced apoptosis, respectively, in HEK293 cells. Interestingly, Nfe2l1 protein stability was more sensitive to cisplatin than that of Nfe2l2. More importantly, the mechanism that silibinin activates Nfe2l1-mediated antioxidant responses was confirmed in a cisplatin-induced AKI model. Silibinin rescued cisplatin-induced Nfe2l1 inhibition by regulating its transcription and post-translational modifications. Taken together, our results reveal a novel mechanism by which silibinin ameliorates cisplatin-induced AKI via activating Nfe2l1-mediated antioxidative response, which provides a new insights to protect patients receiving cisplatin-based cancer treatment against AKI.

顺铂是一种常用于治疗各种实体瘤的一线化疗药物，具有严重的不良反应，尤其是肾毒性，这在很大程度上限制了其临床应用。然而，目前用于预防肾毒性的措施并不理想，因为尚未全面了解顺铂诱导的肾毒性的机制。在这里，我们检查了水飞蓟宾对顺铂诱导的肾毒性的影响，发现水飞蓟宾在顺铂治疗 HEK293 细胞和顺铂诱导的急性肾损伤 (AKI) 模型中发挥细胞保护作用。从机制上讲，水飞蓟宾通过降低 ROS 介导的 MAPK 信号通路激活来改善顺铂诱导的 AKI，这一点通过抑制剂 N-乙酰半胱氨酸得到证实。而且，水飞蓟宾通过抗氧化转录因子核因子 - 红细胞 2 相关因子 1 (Nfe2l1) 而不是 Nfe2l2 对顺铂诱导的 ROS 产生的保护作用介导 HO1 表达。此外，使用 siRNA 或过表达质粒干扰 Nfe2l1 的丰度分别增强或降低了顺铂诱导的 HEK293 细胞凋亡的影响。有趣的是，Nfe2l1 蛋白稳定性对顺铂的敏感性高于 Nfe2l2。更重要的是，水飞蓟宾激活 Nfe2l1 介导的抗氧化反应的机制在顺铂诱导的 AKI 模型中得到证实。水飞蓟宾通过调节其转录和翻译后修饰来挽救顺铂诱导的 Nfe2l1 抑制。综合起来，