NAD+ depletion transdifferentiates the gastric stem cells to intestinal goblet cells in patient-derived gastric organoids

Gastric intestinal metaplasia (GIM) is a progressive lineage reprogramming process characterized by loss of gastric identity and acquisition of intestinal features. Although disruption of NAD + (nicotinamide adenine dinucleotide) homeostasis is closely linked to chronic inflammation, its role in gastric metaplastic conversion remains unclear. Here, we establish the first human-derived organoid model of type III incomplete GIM recapitulating goblet cell differentiation, alongside four complementary mouse models representing distinct etiologies of metaplasia. Across human tissues, organoids, and in vivo models, we identify consistent upregulation of the NAD + -consuming enzyme CD38, resulting in chronic NAD + depletion. We also confirm NAD + loss reduces SIRT1 activity and increases acetylation of the gastric lineage regulator SOX2 at lysine 73, promoting its nuclear export and functional inactivation. The acute NAD + depletion disrupts gastric lineage maintenance programs without immediately inducing CDX2, while sustained metabolic erosion permits stable intestinal commitment, defining a hierarchical model of lineage conversion. In parallel, the supplementation with nicotinamide mononucleotide (NMN) restores NAD + pools, rescues SIRT1 activity, reduces SOX2 acetylation, and reverses metaplastic phenotypes in both human-derived organoids and mouse models. Our findings reveal a CD38–NAD + –SIRT1–SOX2 axis that metabolically drives gastric epithelial identity and position NAD + homeostasis as a potential strategy for intercepting early gastric tumorigenesis.