ALDH1a3 Protects Against Iron Overload-Induced Oxidative Stress and Mitochondrial Impairment in Renal Tubular Epithelial Cells.

Iron overload significantly contributes to chronic kidney disease progression by triggering oxidative stress and mitochondrial impairment via the Fenton reaction. This study investigates the protective role of aldehyde dehydrogenase 1a3 (ALDH1a3), an enzyme that detoxifies reactive aldehydes, in renal iron overload. C57BL/6N mice were fed a 2.25% ferric citrate diet for 24 weeks to establish a chronic model, followed by treatment with the chelator Dimercaprol (DP). In vitro, TCMK-1 cells were subjected to iron intervention with ALDH1a3 overexpression or inhibition. Chronic iron overload induced significant renal iron deposition, lipid peroxidation (elevated MDA, depleted GSH), and mitochondrial structural damage. ALDH1a3 was endogenously upregulated in renal tubular epithelial cells under iron stress. Overexpressing ALDH1a3 significantly enhanced cell viability, suppressed reactive oxygen species and MDA levels, and preserved mitochondrial membrane potential, whereas its inhibition exacerbated cellular damage. Furthermore, DP treatment reduced iron deposition and was associated with increased ALDH1a3 expression. In conclusion, ALDH1a3 acts as a critical endogenous protective factor against iron-induced nephrotoxicity by mitigating oxidative damage and maintaining mitochondrial stability. These findings indicate that ALDH1a3 is a promising potential therapeutic target for the treatment of iron overload-related kidney diseases.