Through comprehensive approaches using Smad3-knockout (Smad3-KO) mouse model of UUO and Smad3-KO mouse embryonic fibroblasts (MEFs), we then investigated the regulatory mechanism of TGF-β/Smad3 signaling in GPX4 expression during the development of renal fibrosis in vivo and in vitro. Here, GPX4 is linked to renal fibrosis.