Blockade of Interferon-Induced Protein 35 Alleviates Cisplatin-Induced Ferroptosis in Acute Kidney Injury Through Activation of the NRF2

Ferroptosis is a non-regulatory cell death closely related to the process of cisplatin-induced acute kidney injury (AKI). We sought to explore the ability of inhibited Interferon-induced protein 35 (IFI35) to alleviate cisplatin-induced AKI by modulating Ferroptosis. Expression of IFI35 was investigated in the cisplatin-induced AKI mouse model and cisplatin-induced HK2 cells. The potential molecular mechanisms were examined in cells by detecting ferroptosis-related indicators following the addition of Ferroptosis inducer (Erastin) and the antioxidant transcription factor NRF2 pathway inhibitor (ML385), respectively. Higher levels of IFI35 were observed in AKI mouse model and HK2 cells. IFI35 deficiency enhanced cell viability and antioxidant capacity, reducing ferroptosis-related parameters like Fe²⁺ accumulation and ROS production while upregulating GPX4 and FSP1 protein levels. In mice, IFI35 blockade attenuated cisplatin-induced renal injury, as evidenced by decreased serum urea nitrogen and creatinine levels, and improved histopathological changes. Mechanistically, IFI35 inhibition reduced peroxide production, reversed iron-dependent mitochondrial damage, and inhibited Ferroptosis via upregulating NRF2 activity. Our study suggested that IFI35 inhibition inhibits Ferroptosis in AKI by upregulating NRF2 expression, targeting IFI35 may offer a promising therapeutic option for AKI.

acute kidney injury; ferroptosis; interferon‐induced protein 35; nuclear factor E2‐related factor 2; renal tubular epithelial cells.