Lessons learned from aldehyde dehydrogenases as non-P450 aldehyde-oxidizing enzymes: implications for the ‘exposome’ and human health

Aldehyde dehydrogenases (ALDHs) are critical enzymes that protect against cellular damage by metabolizing reactive aldehydes derived from both endogenous processes and environmental exposures. Although cytochrome P450 enzymes dominate metabolic toxicology discussions, the non-P450 ALDH superfamily plays a unique underrecognized role in mitigating the health impacts of the exposome - the totality of lifetime environmental exposures. This Special Report highlights key insights from recent research on ALDHs, with a focus on their enzymatic diversity, disease-relevant polymorphisms, detoxication functions, and potential as therapeutic targets and clinical biomarkers. A comprehensive review is provided on how ALDHs influence individual susceptibility to environmental stressors, support redox balance, and serve as important mediators in cancer, cardiovascular and neurodegenerative diseases. Clinical implications of ALDH polymorphisms are discussed in the context of precision environmental health. Whereas ALDHs are generally known for their role in detoxifying harmful aldehydes, some ALDHs have been shown to activate other molecules instead. For example, ALDH2 can activate nitroglycerin to nitric oxide-related species - critical for cardioprotective signaling; a process distinct from their typical detoxication function. Integrating ALDH biology into exposome research offers a powerful path toward precision risk assessment and possible interventions. Given their public health and clinical relevance, future efforts should prioritize mapping ALDH-exposome interactions, genetic screening, and developing ALDH-targeted interventions.