Cell metabolismOct 15, 2026

A flexible approach to targeting cell energy metabolism in cancer

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 16, 2026

Abstract

NAD metabolism may support the preservation of cellular homeostasis against oncogenic insults.

NAD functions as a cofactor for enzymes that regulate DNA repair, epigenetic changes, and inflammation.
Cancer cells may adapt to biosynthetic and genotoxic stress by increasing NAD production through nicotinamide phosphoribosyltransferase (NAMPT).
Enhanced NAD availability is associated with increased cancer cell proliferation, stress tolerance, and immune evasion.
Targeting NAD metabolism with NAMPT inhibitors and PARP inhibitors shows preclinical and some clinical effectiveness in treating cancer.
There are significant barriers to the clinical application of therapies that exploit the dependence of cancer cells on NAD.

Simplified

Nicotinamide adenine dinucleotide (NAD) occupies a privileged position at the intersection of cellular bioenergetics, redox homeostasis, and signal transduction. Beyond its canonical role in ATP synthesis, NAD serves as an obligate cofactor for enzymes including poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, thereby regulating DNA repair, epigenetic remodeling, and inflammatory signaling. Thus, NAD metabolism supports the preservation of cellular homeostasis against oncogenic insults. Malignant transformation, however, imposes substantial biosynthetic and genotoxic stress, often driving metabolic adaptations that amplify NAD production via nicotinamide phosphoribosyltransferase (NAMPT). This endows cancer cells with enhanced proliferative capacity, stress tolerance, and immunoevasive features. Importantly, the dependence of malignant cells on sustained NAD availability constitutes a therapeutically exploitable vulnerability. Accordingly, NAMPT inhibitors, PARP inhibitors, and strategies targeting NAD-consuming ectoenzymes have shown preclinical and, in select settings, clinical efficacy. Here, we critically review the rewiring of NAD metabolism in cancer, associated therapeutic opportunities, and barriers to their clinical exploitation.

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A flexible approach to targeting cell energy metabolism in cancer

Abstract

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