This novel finding was functionally confirmed in the UUO mice and mouse embryonic fibroblasts (MEFs) in which deletion of Smad3 protected against UUO and transforming growth factor-β1 (TGF-β1)-induced loss of GPX4, upregulation of TFR1 and 4-HNE, and progressive renal fibrosis in vivo and in vitro. This evidence concerns the gene SMAD3 and renal fibrosis.