Acute kidney injury (AKI) is primarily caused by renal ischemia-reperfusion injury (IRI), which is one of the most prevalent triggers. Currently, preventive and therapeutic measures remain limited. Ferroptosis plays a significant role in the pathophysiological process of IRI-induced AKI and is considered a key target for improving its outcomes. Silibinin, a polyphenolic flavonoid, possesses diverse pharmacological properties and is widely used as an effective therapeutic agent for liver diseases. Recent studies have reported that silibinin may improves kidney diseases, though the underlying mechanism remain unclear. In this study, we investigated whether silibinin protects against IRI-induced AKI and explored its mechanism of action. Our findings indicated that pretreatment with silibinin alleviated renal dysfunction, pathological damage, and inflammation in IRI-AKI mice. Furthermore, the results demonstrated that silibinin inhibited ferroptosis both in vivo and in vitro. Proteome microarrays were used to identify silibinin's target, and our results revealed that silibinin binds to FTH1. This binding affinity was confirmed through molecular docking, SPRi, CETSA, and DARTS. Additionally, co-IP assays demonstrated that silibinin disrupted the NCOA4-FTH1 interaction, inhibiting ferritinophagy. Finally, the inhibitory effects of silibinin on ferroptosis were reversed by knocking down FTH1 in vitro. In conclusion, our study shows that silibinin effectively alleviates AKI by targeting FTH1 to reduce ferroptosis, suggesting that silibinin could be developed as a potential therapeutic agent for managing and treating AKI.

中文翻译：

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水飞蓟宾通过靶向 FTH1 减轻急性肾损伤中的铁死亡


急性肾损伤 （AKI） 主要由肾缺血再灌注损伤 （IRI） 引起，IRI 是最常见的触发因素之一。目前，预防和治疗措施仍然有限。铁死亡在 IRI 诱导的 AKI 的病理生理过程中起着重要作用，被认为是改善其结果的关键靶点。水飞蓟宾是一种多酚类黄酮，具有多种药理特性，被广泛用作肝病的有效治疗剂。最近的研究报告称，水飞扬宾可以改善肾脏疾病，但其潜在机制仍不清楚。在这项研究中，我们调查了水飞扬宾是否能预防 IRI 诱导的 AKI，并探讨了其作用机制。我们的研究结果表明，水飞扬宾预处理减轻了 IRI-AKI 小鼠的肾功能不全、病理损伤和炎症。此外，结果表明，水飞扬宾在体内和体外均抑制铁死亡。蛋白质组微阵列用于鉴定水飞扬宾的靶标，我们的结果显示水飞扬素与 FTH1 结合。这种结合亲和力通过分子对接、SPRi、CETSA 和 DARTS 得到证实。此外，co-IP 检测表明，水飞扬宾破坏了 NCOA4-FTH1 相互作用，抑制了铁自噬。最后，通过在体外敲低 FTH1 逆转水飞飞扬素对铁死亡的抑制作用。总之，我们的研究表明，水飞扬素通过靶向 FTH1 减少铁死亡而有效缓解 AKI，这表明水飞扬素可以开发为管理和治疗 AKI 的潜在治疗剂。