ALKBH7 mediates the mitigative effect of bismuth drug against cisplatin-induced acute kidney injury.

Cisplatin is a potent chemotherapeutic drug widely used to treat cancers. Unfortunately, its overaccumulation in kidney proximal tubular cell (PTC) results in severe acute kidney injury (AKI). Bismuth drugs have long been used to treat gastrointestinal tract disorder and Helicobacter pylori infection. Interestingly, oral administration of bismuth drugs can also mitigate cisplatin-induced AKI, but the underlying mechanism remains unknown. In this study, we found even low concentrations of bismuth can specifically increase the survival rate of human PTC upon excessive cisplatin exposure. Using multiomics and protein-small molecule interaction techniques, we identified mitochondrial iron-binding protein ALKBH7 as a specific target of bismuth. By gene knockout and silencing, we demonstrated that ALKBH7 depletion indeed greatly increases cell survival rate upon excessive cisplatin exposure. Furthermore, we found bismuth treatment depletes ALKBH7 in mice kidney and prevents cisplatin-induced AKI. Overall, our evidence suggests ALKBH7 is a specific target of bismuth drugs, and ALKBH7 inhibitors are potential drug candidates for mitigation of cisplatin-induced AKI.