Aldehyde dehydrogenase 2 mitigates acrolein-driven ferroptosis to preserve kidney function

Acrolein, a highly reactive aldehyde generated endogenously through lipid peroxidation and exogenously from various environmental sources, is an important mediator of oxidative renal injury. Its accumulation in proximal tubular epithelial cells (PTECs) leads to mitochondrial dysfunction, oxidative stress, and cell death. Aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes; however, the common East Asian ALDH2∗2 (Glu504Lys) variant significantly reduces enzymatic activity, potentially increasing susceptibility to acrolein toxicity. In this study, we demonstrate that acrolein induces ferroptosis and mitochondrial dysfunction in primary mouse PTECs, with more severe cytotoxicity observed in Aldh2∗2 cells compared to wild-type cells. Mechanistically, acrolein increased intracellular iron accumulation, lipid ROS, and lipid peroxidation while disrupting mitochondrial membrane potential, ATP production, and respiratory capacity, collectively driving ferroptotic cell death. Pharmacological inhibition with ferrostatin-1, deferoxamine, or the mitochondrial ROS scavenger MitoTempo mitigated these effects, confirming the involvement of ferroptosis and mitochondrial oxidative stress. Importantly, ALDH2 activators, including Alda-1, and AD-5591, the metabolite of AD-9308, restored ALDH2 activity, reduced oxidative stress, improved mitochondrial function, and rescued cell viability in both genotypes. In vivo, oral AD-9308 treatment significantly alleviated acrolein-induced kidney injury in Aldh2∗2 mutant mice by reducing tubular damage, fibrosis, and inflammation. Collectively, these findings identify ferroptosis as a central mechanism of acrolein nephrotoxicity and highlight ALDH2 activation as a promising therapeutic approach, particularly for individuals carrying the Glu504Lys mutation.