Quercetin Alleviates Ferroptosis-Induced Renal Fibrosis by Modulating the PRDM9/HMOX1/PTGS2 Axis

Abstract Ferroptosis-induced renal fibrosis is a key driver of chronic kidney disease (CKD) progression, yet effective therapies remain limited. This study investigates the therapeutic potential of quercetin (QCT), a bioflavonoid derived from Ginkgo biloba fruit peel, in mitigating ferroptosis-associated renal fibrosis. Network pharmacology identified HMOX1 and PTGS2 as core candidate genes associated with the therapeutic response to QCT in renal fibrosis. In a unilateral ureteral obstruction (UUO)-induced CKD mouse model, QCT treatment attenuated tubular injury, improved renal function, and reduced fibrosis markers such as fibronectin, Col1a1, and α-SMA. Mechanistically, QCT suppressed ferroptosis and epithelial–mesenchymal transition (EMT) by downregulating HMOX1. Further analysis revealed that PRDM9, a histone methyltransferase and transcription factor, drives HMOX1 expression through both transcriptional activation and H3K4me3-mediated epigenetic modification. Knockdown of PRDM9 reduced HMOX1 expression and alleviated fibrosis. These findings highlight a novel epigenetic mechanism underlying ferroptosis-induced renal fibrosis and position QCT as a promising therapeutic candidate for CKD.