Pharmacological activation of aldehyde dehydrogenase 2 inhibits ferroptosis via SLC7A11/GPX4 axis to reduce kidney stone formation

Calcium oxalate (CaOx) kidney stones pose a global health challenge due to their high prevalence and recurrence rates. While cell death mechanisms such as ferroptosis are known to play a crucial role in stone formation, the precise underlying mechanisms remain enigmatic. Aldehyde dehydrogenase 2 (ALDH2) is a metabolic enzyme of the ferroptosis product 4-hydroxy-2-nonenal (4-HNE). However, the function of ALDH2 in kidney stones is poorly understood. In this study, we observed a downregulation of ALDH2 in the stone group. Significantly, the administration of Alda-1, an ALDH2 agonist, notably reduced crystal deposition in the kidneys and hindered crystal adhesion to cells. Furthermore, Alda-1 induced upregulation of SLC7A11 expression, promoting glutathione synthesis, reducing lipid peroxidation accumulation, and lowering Fe²⁺ levels. These collective effects attenuated crystal-induced ferroptosis. However, the renoprotective effects of Alda-1 were inhibited by SLC7A11 siRNA. In conclusion, our study explores the applications of Alda-1 and highlights the potential of targeting ALDH2 as a promising therapeutical strategy for urolithiasis.