Cancer is increasingly recognized as a systems-level disease in which genetic alterations interact with metabolic, epigenetic, transcriptional, post-transcriptional, and microenvironmental regulatory networks. Nicotinamide adenine dinucleotide (NAD⁺) represents an important metabolic interface within these networks because it functions as both a redox cofactor and a substrate for enzymes involved in DNA repair, chromatin regulation, and cellular stress responses. NAD⁺ availability influences poly (ADP-ribose) polymerases (PARPs) and NAD⁺-dependent sirtuins, thereby linking cellular metabolic state with genome maintenance and epigenetic regulation. Emerging evidence also suggests potential connections between NAD⁺ metabolism and RNA regulation, including NAD-capped RNA, although the functional significance of these mechanisms in mammalian cancer remains incompletely established. Here, we examine the interactions among NAD⁺ metabolism, PARP and sirtuin activity, chromatin regulation, mitochondrial stress, RNA regulation, and cellular senescence in cancer. We propose an integrative framework in which NAD⁺ functions as a metabolic interface linking cellular energy state with genome maintenance, epigenetic regulation, and post-transcriptional RNA control. Rather than considering NAD⁺ depletion as a universal driver of cancer or senescence, we propose that changes in NAD⁺ availability may modify cellular responses according to the nature and duration of cellular stress. This hypothesis-generating framework identifies testable relationships among NAD⁺ metabolism, chromatin state, RNA regulation, and cellular phenotype, while distinguishing established mechanisms from those requiring further experimental validation.

NAD⁺, Cancer metabolism, Epigenetic regulation, RNA stability, RNA regulation, PARP, Sirtuins, Cellular senescence, Metabolic stress, Systems biology