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

Bojun Li, Fangyou Lin, Baofeng Song, ShangTing Han, Zehua Ye, Yushi Sun, Peihan Wang, Yuqi Xia, Weimin Yu, Xiangjun Zhou () and Fan Cheng ()
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Bojun Li: Renmin Hospital of Wuhan University
Fangyou Lin: Renmin Hospital of Wuhan University
Baofeng Song: Renmin Hospital of Wuhan University
ShangTing Han: Renmin Hospital of Wuhan University
Zehua Ye: Renmin Hospital of Wuhan University
Yushi Sun: Renmin Hospital of Wuhan University
Peihan Wang: Renmin Hospital of Wuhan University
Yuqi Xia: Renmin Hospital of Wuhan University
Weimin Yu: Renmin Hospital of Wuhan University
Xiangjun Zhou: Renmin Hospital of Wuhan University
Fan Cheng: Renmin Hospital of Wuhan University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62433-2

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