Inhibition of tubular epithelial cells ferroptosis alleviates renal interstitial fibrosis by reducing lipid hydroperoxides and TGF-β/Smad signaling

BackgroundFerroptosis is a non-apoptotic form of regulated cell death that involves an imbalance in the homeostasis of two elements: iron and lipid hydroperoxides. The accumulation of lipid hydroperoxide serves as a key trigger for initiating ferroptosis. Recent studies have identified ferroptosis as a critical pathophysiology contributing to kidney disease progression. However, the specific mechanisms underlying the role of ferroptosis in chronic kidney disease (CKD) have not been elucidated.MethodsTubular epithelial cells (TECs) ferroptosis was evaluated in unilateral ureteral obstruction (UUO) models and in TGF-beta-treated HK-2 cells to explore the relationship between ferroptosis and fibrosis. Ferroptosis inhibitors (ferrostatin-1) and TECs-targeted glutathione peroxidase 4 (GPX4) overexpression in vivo and in vitro were used to investigate the effect and mechanism of TECs ferroptosis on fibrosis progression.ResultsOur findings indicate that ferroptosis is persistently activated during various states of the UUO model. As the results, ferroptosis was identified as a core facilitator of renal interstitial fibrosis in TECs during UUO. The reduction in TECs ferroptosis significantly ameliorated renal fibrosis and maintained the structure in the proximal tubules. Persistent activation of TECs ferroptosis effectively aggravated fibrosis progression through the TGF-beta/Smad pathway.ConclusionsInhibiting ferroptosis effectively rescues the accumulation of profibrotic cytokines, thereby alleviating renal fibrosis. The profibrotic mechanism of ferroptosis is closely related to the TGF-beta/Smad pathway, and targeting ferroptosis and increasing GPX4 expression could be an effective strategy for treating CKD.Graphical AbstractThe occurrence of TECs ferroptosis in CKD is due to an imbalance in iron and lipid regulation, which drives the occurrence of lipid peroxidation and the accumulation of lipid hydroperoxide. One of the primary drivers of ferroptosis, lipid peroxidation, further stimulates TGF-beta/Smad signaling and exacerbates fibrosis progression. Abbreviations: TFRC, transferrin receptor protein 1; DMT1, divalent metal transporter 1; FPN, ferroportin; ACSL4, acyl-CoA synthetase long-chain family 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; GPX4, glutathione peroxidase 4; CTGF, connective tissue growth factor; PDGFB, platelet-derived growth factor subunit b; FGF2, fibroblast growth factor 2; TECs, tubular epithelial cells; CKD, chronic kidney disease. (The figure was drawn with BioRender.)