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Trimetazidine delays autoimmune diabetes in mice by transiently suppressing CD8⁺ T-cell fatty-acid oxidation

ABSTRACT: Type 1 Diabetes Mellitus (T1D) is an organ specific autoimmune disease, which is characterized by persistent hyperglycemia due to immune-mediated destruction of pancreatic islet β cells. Shifting immune cell metabolism is an emerging therapeutic concept. Therefore, we tested whether the fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ) can restrain autoreactive immunity and delay T1D in a non-obese diabetic mouse model. Of note, TMZ is one of only three approved drugs directly targeting cellular metabolism. TMZ acutely increased mitochondrial membrane potential, suppressed FAO and curtailed activation and proliferation of human CD8⁺ T cells. In dysglycemic NOD mice, a clinically approved dose of TMZ delayed progression to T1D, lowered mean glycaemia and reduced islet CD4⁺/CD8⁺ infiltration. scRNA-seq revealed depletion of FAO-high, stress-responsive secretory cells and mitochondrially active stromal cells, indicating improved pancreatic health. However, prolonged exposure elicited compensatory up-regulation of carnitine-palmitoyl-transferase-1A in CD8⁺ subsets, normalized T-cell infiltration and nullified protection. We conclude that TMZ delivers a dampening of initial T-cell pressure and pancreatic stress. Adaptive upregulation of FAO within cells counteracted observed benefits thereby only transiently delaying disease onset. Our work demonstrates that drugs targeting cellular metabolism needs to retain sufficient potency to not be outpaced by immune cells upscaling metabolic pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE301646 | GEO | 2026/02/14

REPOSITORIES: GEO

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