Carbonyl stress promotes ferroptotic susceptibility through lipid metabolic remodeling in renal tubular epithelial cells

Abstract

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide and is characterized by progressive tubular injury, oxidative stress, and metabolic dysregulation. Carbonyl stress, driven by the accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MGO), is increasingly recognized as a contributor to renal dysfunction in diabetes; however, the mechanisms linking MGO to tubular cell injury remain incompletely defined. We investigated whether MGO alters lipid metabolic homeostasis to enhance ferroptotic susceptibility in human proximal tubular HK-2 cells. MGO exposure reduced cell viability and induced mitochondrial morphological changes associated with ferroptosis-related injury. Biochemically, MGO increased intracellular Fe²⁺ accumulation, elevated lipid peroxidation and malondialdehyde levels, and suppressed the antioxidant regulators GPX4 and SLC7A11. Notably, MGO significantly upregulated acyl-CoA synthetase long-chain family member 4 (ACSL4) while reducing stearoyl-CoA desaturase 1 (SCD1), suggesting a lipid metabolic shift that may favor an oxidation-prone cellular state. Pharmacological inhibition of ACSL4 attenuated lipid peroxidation, reduced Fe²⁺ accumulation, partially restored antioxidant protein expression, and improved cell viability, supporting the involvement of ACSL4-associated lipid metabolic alterations. Collectively, these findings indicate that carbonyl stress disrupts lipid metabolic balance in renal tubular epithelial cells and enhances ferroptosis-associated vulnerability. This mechanistic framework provides insight into how MGO accumulation may contribute to tubular injury in the context of diabetic kidney disease.