CD38 in hepatic pathobiology: mechanisms, disease association and therapeutic implications.

CD38 is a highly conserved multifunctional enzyme that regulates intracellular calcium signaling and NAD⁺ metabolism. Although extensively studied in cancer and autoimmune diseases, growing evidence points to a critical role for CD38 in both normal and diseased liver physiology. In hepatic tissue, CD38 is expressed on multiple cell types. Aberrant CD38 activity contributes to increased oxidative stress, inflammation, and diminished tissue repair. Recent studies suggest that CD38 may also promote cellular senescence partly through its regulation of intracellular NAD⁺ and calcium. This review examines the role of CD38 in maintaining hepatic homeostasis and explores its involvement in liver injury, chronic liver diseases, and carcinogenesis. We also highlight the contribution of CD38-mediated signaling to hepatic fibrogenesis and end-stage liver failure as well as its potential role in liver transplantation, particularly post-transplant related conditions including ischemic injury and acute cellular rejection. Given its impact on multiple intracellular processes, CD38 has emerged as a promising therapeutic target. New findings describe how CD38 inhibition preserves NAD⁺ levels, supports tissue recovery, and mitigates disease progression in the liver. Finally, we outline new frontiers for CD38 in liver biology and the advancement of CD38-targeted therapeutic strategies.