CD38 Inhibitors Restore NAD+ Levels to Fight Aging and Disease

NAD+ is indispensable for cellular energy metabolism, sirtuin-mediated gene regulation, PARP-driven DNA repair, and immune signaling. Its levels decline progressively with age, and CD38—a type II transmembrane ectoenzyme—has been identified as the principal driver of that decline. CD38's glycohydrolase activity cleaves NAD+ far more efficiently than competing enzymes such as sirtuins and PARPs, converting it into ADP-ribose and cyclic ADP-ribose, potent calcium-mobilizing second messengers. When CD38 activity is chronically elevated, as occurs during aging, chronic inflammation, and in tumor microenvironments, the resulting NAD+ depletion impairs mitochondrial biogenesis, blunts sirtuin signaling, and suppresses effector immune cell function.

This 2026 review from the Zhang laboratory at the University of Southern California systematically surveys the pathophysiological contexts in which CD38 contributes to disease. In multiple myeloma (MM), uniformly high CD38 expression on malignant plasma cells drives an immunosuppressive adenosinergic cascade—via CD203a and CD73—that shields tumor cells from cytotoxic T and NK cell attack. Anti-CD38 monoclonal antibodies daratumumab and isatuximab exploit this expression pattern therapeutically. In solid tumors such as hepatocellular carcinoma and non-small cell lung cancer, elevated CD38 correlates with acquired resistance to PD-1/PD-L1 checkpoint inhibitors, suggesting enzymatic CD38 blockade could sensitize tumors to immunotherapy. In aging tissues, accumulation of CD38-positive senescent cells and M1 macrophages is a major mechanistic driver of systemic NAD+ loss, impaired SIRT1/SIRT3 activity, and metabolic fragility. In autoimmune diseases including rheumatoid arthritis and SLE, CD38-high plasmablasts and plasma cells sustain pathogenic autoantibody production through NF-κB and STAT1/3 signaling.

The core contribution of this review is its chemical taxonomy of CD38 small-molecule inhibitors. Covalent inhibitors—mechanism-based nucleotides and nucleosides—exploit the enzyme's catalytic Glu226 residue to form stable ADP-ribosyl-enzyme intermediates, achieving potent and durable inhibition. Non-covalent inhibitors span several structural classes: NAD+ analogues that occupy the substrate-binding pocket competitively; synthetic heterocycles and scaffolds identified through rational design or high-throughput screening; and natural products with diverse pharmacophores. Each class presents distinct potency, selectivity, and drug-likeness profiles, providing a rich chemical landscape for optimization.

From a longevity and translational perspective, the implications are significant. Genetic deletion or pharmacological inhibition of CD38 in preclinical models consistently restores tissue NAD+ levels, enhances mitochondrial respiration, reactivates sirtuin pathways, and improves metabolic and immune outcomes in aged or inflamed tissues. These effects parallel—and may synergize with—NAD+ precursor supplementation strategies (NMN, NR), though CD38 inhibition addresses the degradation side of the NAD+ equation directly.

Caveats include the review's preclinical focus: most inhibitor data derive from enzymatic assays and cell-based models, with limited in vivo pharmacokinetic or safety characterization for the majority of compounds. Selectivity over related ADP-ribosyl cyclases (CD157, SARM1) and NAD+-consuming enzymes (PARPs, sirtuins) requires careful validation. The dual role of CD38 as both enzyme and receptor, and its context-dependent expression on effector versus regulatory immune cells, adds complexity to therapeutic targeting strategies.