Mol Cell

Formaldehyde (FA) is an environmental pollutant and an endogenous metabolite produced in cells from central metabolic pathways. It rapidly reacts with electron-rich groups in biomolecules like nucleic acids and proteins, leading to cellular damage. Recent studies have revealed regulatory roles of FA in one-carbon metabolism, and its impact on cellular redox homeostasis and differentiation processes. Additionally, new insights have emerged into the molecular mechanisms underlying the repair of FA-induced DNA-protein and RNA-protein crosslinks. These processes are relevant to human conditions associated with inherited mutations in genes coding for FA-counteracting factors such as Fanconi anemia and AMeD, Ruijs-Aalfs, and Cockayne syndromes. This work examines these emerging mechanistic advances in FA biology, discusses their implications for human health, and highlights unresolved questions in the field.