Curcumol Ameliorates Diabetic Nephropathy by Inhibiting Podocyte Ferroptosis Through the xCT/GPX4 Pathway.

Abstract

BACKGROUND: Diabetic nephropathy is a leading complication of diabetes mellitus and poses a significant public health challenge. Ferroptosis has emerged as a critical pathological factor that exacerbates the progression of diabetic nephropathy. While previous studies have demonstrated the antiferroptotic effects of curcumol (Cur), its therapeutic potential in treating diabetic nephropathy, along with the underlying mechanisms, remains to be fully elucidated. METHODS: To investigate this, we established a high glucose-induced MPC-5 cell injury model. Initially, we identified the safe concentration range of curcumol. Using Western blot (WB) analysis and transcriptomic profiling, we assessed target proteins and regulatory pathways, and systematically measured ferroptosis-related biomarkers. To further explore Cur's effect on ferroptosis, we cotreated the in vitro model with the ferroptosis inhibitor Fer-1 and activator RLS3, analyzing the key pathways involved using WB and transcriptomic approaches. Additionally, we established a diabetic kidney disease (DKD) mouse model to assess the effects of Cur on renal function indicators, including serum creatinine, urea nitrogen, and 24-h urinary protein levels. Renal pathological changes and molecular markers were evaluated, and the core pathway mechanisms were validated by WB analysis. RESULTS: In in vitro experiments, Cur reduced iron deposition and total iron content by downregulating TRF and NCOA4. It also inhibited ACSL4-mediated lipid peroxidation, resulting in lower levels of ROS, MDA, and 4-HNE. Additionally, Cur upregulated the expression of SLC3A2, SLC7A11, and GPX4, thereby restoring the GSH-GPX4 antioxidant system. In vivo, Cur improved renal function and alleviated renal injury in DKD mice through the xCT/GPX4 signaling pathway. These findings suggest that Cur mitigates ferroptosis via the xCT/GPX4 pathway, ultimately slowing the progression of diabetic kidney disease. CONCLUSION: Our in vitro and in vivo experiments demonstrate that Cur has therapeutic potential for DKD. Mechanistically, Cur protects against podocyte ferroptosis by modulating the xCT/GPX4 pathway.