Smad3 Mediates Renal Fibrosis via GPX4-Dependent Ferroptosis.

ABSTRACT: TGF-β/Smad3 signaling is a key pathway leading to the cell death and renal fibrosis. Here we report a new mechanism through which Smad3 mediates renal fibrosis by downregulating the glutathione peroxidase 4 (GPX4), a central inhibitor for ferroptosis. In patients with chronic kidney disease (CKD) and a mouse model of unilateral ureteral obstruction (UUO), progressive renal fibrosis was associated with the overactive Smad3 signaling and the development of ferroptosis identified by decreased GPX4 while increasing two ferroptosis biomarkers including the Transferrin receptor 1 (TFR1) and 4-Hydroxynonenal (4-HNE). Mechanistically, we uncovered that Smad3 could bind directly to GPX4 to repress its transcription while increasing TFR1 and 4-HNE expression, which was abolished when this binding si

SUBMITTER: Liu K 

PROVIDER: S-EPMC12509913 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature