Department of Traditional Chinese Medicine, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310005, China.
Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310005, China.
Cell Biol Toxicol. 2024 Nov 18;40(1):99. doi: 10.1007/s10565-024-09947-5.
In the clinical setting, cisplatin-induced nephrotoxicity primarily manifests as acute kidney injury (AKI). Recent studies have indicated that ferroptosis, a type of iron-dependent cell death, is closely involved in the cisplatin nephrotoxicity. AlkB homologue 5 (ALKBH5), an N6-methyladenosine (m6A) eraser protein expressed in various tissues, including the kidneys, has been implicated in this process. However, the specific role of ALKBH5 in cisplatin-induced nephrotoxicity remains unknown. Our findings indicated that ALKBH5 was upregulated in cisplatin-induced AKI, and the in vivo study results were consistent with the results of the in vitro study. Additionally, ALKBH5 knockout in transgenic animals was found to mitigate cisplatin-induced renal dysfunction, whereas its knock-in exacerbated the effects. Our study revealed that ALKBH5 controls the traditional ferroptosis metabolic pathway, leading to worsening of AKI in experiments conducted both in vivo and in vitro. The efficacy of pharmacological intervention targeting ALKBH5 in AKI animal models was demonstrated, and ALKBH5-based gene therapy confirmed these findings and displayed renoprotective effects against AKI. In conclusion, this study highlighted the crucial role of ALKBH5 as a key regulator of AKI. Overall, our research demonstrates the significant impact of ALKBH5 in controlling ferroptosis in cisplatin-induced AKI, suggesting that focusing on ALKBH5 could be a promising approach for treating cisplatin-related kidney damage.
在临床环境中，顺铂引起的肾毒性主要表现为急性肾损伤（AKI）。最近的研究表明，铁依赖性细胞死亡的一种类型——铁死亡，与顺铂肾毒性密切相关。在包括肾脏在内的各种组织中表达的 N6-甲基腺苷（m6A）去甲基化酶蛋白 AlkB 同源物 5（ALKBH5），已被认为与该过程有关。然而，ALKBH5 在顺铂诱导的肾毒性中的具体作用尚不清楚。我们的研究结果表明，ALKBH5 在顺铂诱导的 AKI 中上调，体内研究结果与体外研究结果一致。此外，在转基因动物中敲除 ALKBH5 被发现减轻了顺铂诱导的肾功能障碍，而其敲入则加剧了这种作用。我们的研究表明，ALKBH5 控制着传统的铁死亡代谢途径，导致体内和体外实验中 AKI 的恶化。针对 AKI 动物模型中 ALKBH5 的药理学干预的疗效得到了证实，基于 ALKBH5 的基因治疗也证实了这些发现，并显示出对 AKI 的肾脏保护作用。总之，这项研究强调了 ALKBH5 作为 AKI 关键调节剂的重要作用。总的来说，我们的研究表明，ALKBH5 在控制顺铂诱导的 AKI 中铁死亡方面具有重要作用，提示针对 ALKBH5 可能是治疗顺铂相关肾损伤的一种有前途的方法。
