Deubiquitinase USP35 regulates MDM4 degradation to promote endothelial ferroptosis and renal injury progression

Cisplatin is a widely used chemotherapeutic drug for various types of malignant tumors, but its nephrotoxic side effects limit its clinical application. There have been numerous reports and studies on cisplatin-induced acute kidney injury (AKI). Through transcriptomic and single-cell analyses, we found that USP35 is highly expressed in AKI and is closely related to MDM4. We investigated the role and mechanism of USP35-mediated MDM4 ubiquitination in AKI using renal epithelial cells and animal models. In a kidney-specific USP35 knockout model, AKI was significantly improved, and endothelial ferroptosis was inhibited. Overexpression of USP35 can promote AKI and endothelial ferroptosis. USP35 induces the autophagic degradation of MDM4 following deubiquitination, which activates the P53 signaling pathway mediating endothelial ferroptosis. We propose that the USP35-MDM4-P53 signaling pathway plays an important role in AKI and indicates that USP35 is a potential therapeutic target for AKI.