The malate–aspartate shuttle in gastric atrophy and precancerous progression: an emerging redox–bioenergetic axis

Gastric atrophy is a precursor of intestinal-type gastric cancer and is associated with mitochondrial and metabolic abnormalities. The malate–aspartate shuttle (MAS) couples cytosolic NADH oxidation to mitochondrial metabolism and intersects with glycolysis, the tricarboxylic acid cycle, aspartate metabolism, and biosynthesis. This review distinguishes direct gastric observations from mechanistic evidence obtained in other systems. Gastric studies report heterogeneous mitochondrial, metabolite, and component-level findings in different histological and etiological settings. Prospective tissue and plasma omics studies identify progression-associated signatures, but do not establish a longitudinal MAS trajectory, and integrated shuttle function remains unresolved in gastric atrophy and intestinal metaplasia. We consider three context-dependent interpretations: secondary remodeling, a maladaptive contribution to injury, and protective adaptation. These roles may coexist or change over time rather than form mutually exclusive categories. Distinguishing them requires defined baseline functional changes, bidirectional perturbations under matched upstream stress, compartment-resolved redox measurements, and complementary enzyme/carrier interventions linked to gastric phenotypes. Reconstituted shuttle activity must also be distinguished from endogenous flux in intact cells. The MAS provides a hypothesis-generating framework for gastric redox–bioenergetic research; its disease-stage behavior, causal significance, and therapeutic direction require direct validation.