Quercetin Alleviates Folic Acid-Induced Renal Fibrosis by Inhibiting Tubular Epithelial Cell Ferroptosis via EGFR/ACSL4 Pathway

Ferroptosis has emerged as a critical contributor to the pathogenesis of chronic kidney disease (CKD). Quercetin, a promising therapeutic agent and flavonoid with potential antiferroptotic properties, has demonstrated renoprotective effects. However, its molecular mechanisms remain unclear. This study integrated bioinformatics, network pharmacology, and molecular docking to identify the epithelial growth factor receptor (EGFR) as a key target of quercetin. In folic acid (FA)-induced CKD mice, quercetin decreased renal fibrosis (reducing [Formula: see text]-SMA, collagen I, and fibronectin), suppressed ferroptosis markers (including iron accumulation, malondialdehyde [MDA] levels, and acyl-CoA synthetase long-chain family member 4 [ACSL4] expression), and downregulated EGFR. In FA-stimulated HK-2 cells, quercetin inhibited epithelial-mesenchymal transition (by decreasing N-cadherin and fibronectin) and ferroptosis (by lowering iron, MDA, and ACSL4) while suppressing EGFR expression. Pharmacological inhibition and genetic knockout of EGFR in HK-2 cells confirmed that EGFR blockade alleviated FA-induced renal fibrosis and ferroptosis. These findings demonstrate that quercetin mitigates FA-induced renal fibrosis by inhibiting tubular epithelial ferroptosis via the EGFR/ACSL4 signaling axis, and thus highlights its therapeutic potential in CKD.