ALKBH5 insufficiency protects against ferroptosis-driven cisplatin-induced renal cytotoxicity.

Abstract

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.