Beyond redox: vitamin C in signaling, epigenetic regulation and protein modification—relevance to cancer therapy

Vitamin C, a classical antioxidant, is increasingly recognized as a key regulator of cellular signaling networks, epigenetic, and post-translational regulation. As a cofactor of Fe 2+ /2-oxoglutarate-dependent dioxygenases, vitamin C promotes epigenomic changes by enhancing TET-dependent DNA demethylation and the activity of Jumonji-C domain-containing histone demethylase, thereby influencing key cellular processes including pluripotency, reprogramming, and differentiation. Recent studies have also uncovered a direct role for vitamin C in proteome regulation by modifying lysine residues, to generate vitcyl-lysine (a process termed as Vitcylation), opening new avenues for its therapeutic applications. These lesser-understood functions of vitamin C underpin its context-dependent roles in cancer and other disease states. Future mechanistic studies identifying targets of vitamin C-dependent protein modification and their consequences on epigenome regulation will be critical for advancing its therapeutic applications.