The long non-coding RNA RSDR protects against acute kidney injury in mice by interacting with hnRNPK to regulate DHODH-mediated ferroptosis

Acute kidney injury (AKI) is a serious clinical condition whose underlying mechanisms remain unclear. Here we identify a long non-coding RNA, RSDR, as a critical regulator of renal protection in AKI. RSDR interacts with the RNA-binding protein hnRNPK, forming a positive feedback loop that enhances the transcription of DHODH, a key ferroptosis-suppressing gene. Mechanistically, RSDR promotes the nuclear retention of hnRNPK and facilitates epigenetic activation of DHODH, thereby limiting ferroptosis in renal tubular epithelial cells. In vivo overexpression of RSDR attenuates ferroptosis and preserves renal function in male mice during AKI. Clinically, urinary RSDR levels are significantly reduced in patients with AKI, and machine learning analysis suggests potential utility in disease detection. These findings highlight RSDR as a central regulator of ferroptosis and provide mechanistic insights into lncRNA-mediated tubular protection in AKI. Ferroptosis has been reported to contribute to the pathogenesis of acute kidney injury (AKI). Here the authors report a study with male mice showing that the long non-coding RNA RSDR suppresses renal tubular cell ferroptosis in AKI by retaining nuclear hnRNPK and activating DHODH transcription