Methylglyoxal Drives Renal Tubular Ferroptosis by Disrupting Redox Homeostasis: Integrated Assessment of Antioxidant Biomarkers in Experimental Kidney Injury Models

Methylglyoxal (MGO), which is a highly reactive dicarbonyl compound, has been increasingly recognized due to its role in the pathogenesis of kidney injury, particularly in diseases such as diabetic nephropathy and hypertensive nephropathy. MGO promotes advanced glycation end product (AGE) formation and directly impairs cell function. MGO levels are significantly increased in various renal diseases. This study aimed to investigate the relationship between MGO and ferroptosis, which is a form of cell death involving iron-dependent lipid peroxidation (LPO), during kidney injury. Animal and cellular experiments were conducted to verify that ferroptosis occurred after MGO treatment, and RNA sequencing (RNA-Seq) was performed to analyse changes in gene expression profiles after MGO exposure. A mouse model that mimicked human kidney injury was established by administering folic acid, and the MGO and D-lactate levels in serum and tissues were measured. In vitro experiments involved treating human HK-2 renal tubular epithelial cells (TECs) with MGO and assessing markers of cytotoxicity, oxidative stress, and ferroptosis. MGO levels were significantly increased in serum and renal tissues from patients with renal injury and from model mice. In HK-2 cells, MGO treatment induced cytotoxicity, increased intracellular reactive oxygen species (ROS) levels, triggered ferroptosis by increasing LPO, and decreased glutathione (GSH) levels. These findings confirm the link between MGO accumulation and kidney injury and indicate that MGO promotes ferroptosis specifically in renal TECs. This study provides new insights into the molecular mechanisms underlying MGO-induced kidney injury and potential directions for developing new therapeutic strategies.