The Major Iron Transporter DMT1 Promotes Renal Fibrosis by Activating Ferroptosis and Enforcing TGF-β1 Signaling in Renal Tubular Cells

Introduction: Renal fibrosis is a common pathological feature of chronic kidney disease (CKD), but effective therapies are still lacking. Ferroptosis has been increasingly associated with CKD; however, the iron-handling proteins that link ferroptotic stress to fibrotic signaling remain poorly defined. Here, we identify the divalent metal transporter 1 (DMT1) as a previously unrecognized regulatory factor that integrates iron metabolism, ferroptotic stress, and transforming growth factor-beta (TGF-β) signaling in tubular epithelial cells (TECs). Results: DMT1 expression was elevated in TECs from folic acid injection- or unilateral ureteral obstruction-induced mouse CKD models and in isolated primary TECs exposed to TGF-β1 or palmitic acid, accompanied by increased mitochondrial reactive oxygen species (mtROS) production. Pharmacological inhibition or genetic deletion of DMT1 in TECs significantly attenuated renal fibrosis, with reduced renal fibrosis area, decreased expression of profibrotic genes and markers, lower mtROS production, and restored fatty acid oxidation. DMT1 deficiency also attenuated lipid peroxidation, with reduced 4-HNE levels and lipid droplet deposition in mouse CKD models. Additionally, DMT1 deletion reduced tissue iron content, reversed ferroptosis-associated morphological changes in TECs, and restored tissue glutathione peroxidase-4 expression. Notably, DMT1 deletion reduced both total Smad2 and phosphorylated Smad2 induced by TGF-β1, consistent with suppression of the TGF-β1–Smad axis. Innovation and Conclusions: These findings support a model in which tubular DMT1 integrates iron overload, ferroptotic stress, and TGF-β1–Smad signaling during fibrotic progression in CKD. DMT1 functions as a signaling hub contributing to TGF-β1–Smad axis activation, although a direct causal chain from iron influx to transforming growth factor beta receptor 1 induction remains to be fully delineated. DMT1 inhibition may offer a tubular-selective therapeutic strategy for CKD. Antioxid. Redox Signal. 00, 000–000.