F-box only protein 10 protects against kidney tubulointerstitial fibrosis by inhibiting ACSL4-mediated lipid peroxidation and ferroptosis

Renal tubular epithelial cell ferroptosis is significantly linked to kidney tubulointerstitial fibrosis, a critical pathological condition in chronic kidney disease. F-box only protein 10 (FBXO10), a newly identified ferroptosis-regulating gene, plays a role in various pathological contexts; however, its involvement in kidney tubulointerstitial fibrosis is not yet fully understood. This research sought to investigate whether FBXO10 regulates ferroptosis in kidney tubular epithelial cells and its relationship with kidney tubulointerstitial fibrosis in both animal and cellular models. We observed a significant decrease in FBXO10 levels in mice with unilateral ureteral obstruction (UUO) and HK-2 cells exposed to TGF-β1. FBXO10 overexpression inhibited the EMT process and counteracted the typical ferroptosis features evoked by TGF-β1 or erastin in HK-2 cells. Compared with those in wild-type (WT) mice, kidney injury, inflammation, and fibrosis are exacerbated in FBXO10-knockout (KO) mice, with elevated ferroptosis levels. Conversely, FBXO10 overexpression reversed these symptoms, alleviating kidney fibrosis and ferroptosis in both WT and FBXO10 KO mice with UUO. Mechanistically, FBXO10 directly interacted with ACSL4 and promoted its ubiquitination and degradation. Overexpression of ACSL4 reversed the inhibitory effect of FBXO10 overexpression on TGF-β1-induced ferroptotic death and fibrosis in HK-2 cells. In summary, FBXO10 mitigates ferroptosis in renal tubular epithelial cells by inhibiting ACSL4-mediated lipid peroxidation, thereby hindering the progression of kidney tubulointerstitial fibrosis. FBXO10 is proposed as a promising target for treating kidney disorders related to tubulointerstitial fibrosis.