VAV3 antagonizes Skeletal Muscle Disulfidptosis to maintain Glucose Homeostasis in Type 2 Diabetes

The emergence and progression of type 2 diabetes mellitus (T2DM) are intricately linked to skeletal muscle loss, yet the exact mechanisms remain elusive. Here, our whole-exome and transcriptomic results indicate that VAV3 is mutated and down-regulated in T2DM patients associated with increased sulfur metabolism. Integrated analysis of human transcriptomics, mouse and cellular proteomics, glycol-metabolomics analyses suggest a potential association between VAV3, T2DM and disulfidptosis. Inhibiting disulfidptosis or SLC7A11/3A2 rescues death of Vav3-deleted cells and IR cells. Mechanistically, Vav3 deletion leads to decreased mitochondrial ATP synthesis and reduced GLUT4 expression. Insufficient glucose intake combined with elevated SLC7A11/3A2 expression induces NADPH depletion and cystine accumulation, leading to redox system imbalance and aberrant disulfide bonds formation. This results in F-actin collapse, broken fiber bundles and rapid cell death. Together, our findings reveal unexpected roles of VAV3 in regulating glucose metabolism, disulfidptosis and provide a therapeutic strategy to target skeletal muscle disulfdptosis in T2DM treatment.