NSUN5 Attenuates Renal Injury and Ferroptosis in Hyperuricaemic Nephropathy Through YBX2‐Dependent Stabilisation of SCD1 m5C Methylation

ABSTRACT RNA 5‐methylcytosine (m5C) modification plays a critical role in multiple diseases; however, its function in hyperuricaemic nephropathy (HN) remains unclear. Here, we show that renal m5C levels are markedly decreased and the m5C methyltransferase NOP2/Sun RNA methyltransferase 5 (NSUN5) is downregulated in HN mice. Conditional knock‐in (cKI) mice and mouse tubular epithelial cells overexpressing NSUN5 exhibit resistance to uric acid (UA), thereby alleviating kidney injury, inflammation, and fibrosis in HN. Bisulphite sequencing coupled with RNA sequencing identifies stearoyl‐CoA desaturase‐1 (SCD1) as a direct NSUN5 target and reveals the involvement of NSUN5 in ferroptosis regulation. Mechanistically, NSUN5 installs m5C on SCD1 mRNA. The m5C reader YBX2 binds to the modified transcript, prolonging the half‐life of SCD1 mRNA and enhancing its stability, thereby suppressing ferroptosis. Elevated SCD1 also inhibits NF‐κB p65 phosphorylation and nuclear translocation, dampens inflammatory responses and promotes ABCG2‐dependent UA excretion. Recombinant NSUN5 further ameliorates renal injury in HN. Our findings revealed a novel NSUN5‐mediated mechanism and highlight a potential therapeutic target for HN.