This technology identifies the gut-wall FcRn–IgG axis as a novel therapeutic target underlying “metabolic inertia,” in which lipid dysregulation persists even after dietary improvement. Gut-directed disruption of FcRn–IgG interactions prevents post-diet triglyceride deterioration and may reset the gut’s metabolic memory. In vivo proof-of-concept studies further demonstrate metabolic benefits without detectable systemic IgG depletion, providing a mechanism-distinct therapeutic strategy for lipid dysregulation, obesity recurrence, and metabolic liver disease.