Emerging chemical strategies for CD38 inhibition: restoring NAD+ metabolism and disease control.

Cluster of differentiation 38 (CD38) is a multifunctional ectoenzyme regulating immune functions, calcium signaling, and nicotinamide adenine dinucleotide (NAD+) metabolism. Through rapid hydrolytic degradation of NAD+, CD38 drives cellular NAD+ depletion during aging, inflammation, and tumor growth, contributing to mitochondrial dysfunction and immune suppression. Consequently, CD38 inhibition has been emerging as a potential approach for disease control by restoring NAD+ homeostasis and immunometabolic balance. This review summarizes current advances in the development of small-molecule CD38 inhibitors. Mechanism-based nucleotides and nucleosides enable potent inhibition of CD38 in a covalent manner. From NAD+ analogues and synthetic molecules to natural products, non-covalent inhibitors represent versatile strategies for elevating tissue NAD+ levels with great efficacy by blocking CD38 catalysis. These discoveries establish a diverse chemical landscape for CD38 modulation and provide tools for studying CD38 biology as well as insight into the identification of therapeutic candidates with promising pharmacological activities.