C/EBPα-mediated ACSL4-dependent ferroptosis exacerbates tubular injury in diabetic kidney disease

Diabetic kidney disease (DKD) is a prevalent and debilitating complication of diabetes characterized by progressive renal function decline and a lack of effective treatment options. Here, we investigated the role of the transcription factor CCAAT/enhancer binding protein alpha (C/EBP alpha) in DKD pathogenesis. Analysis of renal biopsy samples revealed increased C/EBP alpha expression in patients with DKD. Using RNA sequencing and proteomics, we explored the mechanisms through which the C/EBP alpha contributes to DKD. Our findings demonstrated that C/EBP alpha exacerbated tubular injury by promoting acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. We identified that C/EBP alpha upregulated ACSL4 expression by binding to its transcription regulatory sequence (TRS), leading to elevated lipid peroxidation and ferroptosis. Furthermore, inhibition or genetic ablation of C/EBP alpha attenuated ferroptosis and mitigated tubular injury in DKD. These results highlighted the C/EBP alpha-ACSL4-ferroptosis pathway as a promising therapeutic target for DKD treatment.