Aldehyde Detoxification in Cancer: Metabolic Guardians of the Genome

Reactive aldehydes are potent electrophiles that damage DNA and can ultimately promote cancer. While many aldehydes are ubiquitous in the environment, mammalian metabolism also generates high levels of endogenous aldehydes sufficient to threaten genome integrity. To protect against these aldehyde genotoxins, mammalian cells rely on diverse families of aldehyde detoxification enzymes as well as DNA repair pathways. Here, we review how aldehyde detoxification safeguards genome integrity, focusing on the aldehyde dehydrogenase (ALDH) family, alcohol dehydrogenase 5 (ADH5), and the glyoxalases. We discuss how these enzymes operate in a 2-tier model (in which tier 1 detoxification enzymes cooperate with tier 2 DNA repair pathways in a tissue-specific manner), the consequences for cancer initiation and progression when aldehyde detoxification is compromised, and the opportunities for targeting aldehydes in cancer therapy.