Metformin alleviates renal tubular injury in diabetic kidney disease by activating mitophagy and inhibiting ferroptosis via HIF-1α/MIOX axis.

Renal tubular injury has emerged as a critical factor in the progression of diabetic kidney disease (DKD). Given renal tubules' high mitochondrial density and susceptibility to mitochondrial dysregulation and ferroptosis, targeting these pathways could offer therapeutic potential. Metformin (MET), a first-line therapy for type 2 diabetes mellitus (T2DM), exerts reno-protective effects by improving mitochondrial function and attenuating fibrosis; however, its role in regulating ferroptosis in DKD remains unclear. This study aimed to investigate the role of MET in modulating mitophagy and ferroptosis in diabetic kidneys. In diabetic mouse models, MET notably alleviated tubular injury by promoting mitophagy and reducing ferroptosis, as shown by increasing levels of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin, while decreased levels of malondialdehyde (MDA) and iron content. Mechanistically, MET downregulated the hypoxia-inducible factor-1alpha (HIF-1α)/myo-inositol oxygenase (MIOX) signaling axis in renal tubular epithelial cells (RTECs), thereby restoring mitophagy and inhibiting ferroptosis. These findings demonstrate that MET mitigates diabetic renal injury by promoting mitophagy and countering ferroptosis via suppressing the HIF-1α/MIOX pathway, highlighting its potential as a therapeutic intervention for halting DKD progression.