Importantly, we also found that GPX4 was a downstream target gene of Smad3 and functioned to protect against Smad3-mediated renal fibrosis as silencing GPX4 restored UUO-induced severe renal fibrosis in Smad3 KO mice and in TGF-β1-stimulated Smad3 KO MEFs and SIS3-treated HK-2 cells. This evidence concerns the gene TGFB1 and renal fibrosis.