Screening for medicine and food homologous ingredients targeting ALDH2 to alleviate acute ethanol-induced liver injury

Background Alcoholic liver disease (ALD) is a major global health burden with limited therapeutic options. Aldehyde dehydrogenase 2 (ALDH2) plays a critical role in alcohol metabolism, and ALDH2 deficiency exacerbates alcohol-induced hepatic injury. Aim This study aimed to identify and validate natural ALDH2 activators from medicine and food homologous sources for alleviating acute ethanol-induced liver injury. Methods A literature-based screening revealed 18 candidate compounds. In vitro enzyme kinetics, molecular docking, and isothermal titration calorimetry were employed to identify four potent ALDH2 activators from these 18 candidates. The hepatoprotective effects of the four candidates were validated in vivo using serum biochemical analyses, oxidative stress measurements, and histopathological examinations in the Gao-binge ALD mouse model. Results Puerarin, sophoricoside, quercetin, and daidzin were preliminarily identified as mixed-type ALDH2 activators, which increased the acetaldehyde dehydrogenation rate catalyzed by ALDH2. These compounds significantly improved motor coordination, reduced blood ethanol and acetaldehyde levels, attenuated hepatic steatosis, normalized transaminase activities, restored antioxidant capacity, and ameliorated liver histopathological damage in the mouse model. Conclusion Several natural ALDH2 activators from medicine and food homologous sources with potent hepatoprotective effects were identified, providing the scientific basis for developing healthy foods and dietary supplements to alleviate acute ethanol-induced liver injury.