Abstract
<title>Abstract</title> <p>Dysregulated glucose and lipid metabolism drives β-cell failure, a central event in type 2 diabetes (T2D) pathogenesis; however, effective mechanisms to preserve β-cell mass remain elusive. Through comprehensive metabolomic profiling of human serum, we identified itaconate as a novel metabolic biomarker reduced in T2D patients in a disease severity–dependent manner. Genetic ablation of itaconate in mice accelerated T2D onset under diabetogenic conditions, whereas pharmacological itaconate supplementation delayed disease progression and maintained glycemic homeostasis with superior efficacy compared to metformin. Mechanistically, we uncovered a previously unrecognized regulatory axis wherein itaconate covalently alkylates RIPK3 at C360, suppressing T231/S232 phosphorylation and thereby blocking necroptosis—the predominant β-cell death pathway triggered by glucolipotoxicity. These findings establish C360 alkylation of RIPK3 as a druggable metabolic checkpoint linking itaconate signaling to β-cell survival, and position itaconate supplementation as a promising disease-modifying strategy for T2D prevention.</p>