Targeting the underlying immune mechanism of diabetes-induced myocardial dysfunction via modulation of SIRT-3/p53/TIGAR/PFKFB-3 and SIRT-3/NF-κB signaling pathways as a potential controlling strategy.

The current study explored the potential of methotrexate (MTX) to target type 2 diabetes (T2D)-induced immune response and mitigate the associated myocardial dysfunction, focusing on the modulation of SIRT3-related pathways. T2D was induced in Sprague Dawley rats via a high-fat diet and fructose feeding for 30 days, followed by streptozotocin injection (35 mg/kg, i.p). Rats were treated with low doses of MTX (1 & 2 mg/kg) twice weekly for two weeks after diabetes induction. Treatment with MTX improved myocardial structure and decreased serum markers of injury. MTX attenuated oxidative stress, restored antioxidant capacity, suppressed NF-κB-driven inflammation, and reduced TGF-β-mediated fibrotic changes. Notably, MTX upregulated cardiac SIRT3 and PFKFB3 expression while downregulating p53/TIGAR signaling pathways, indicating an improvement in T2D-induced glycolytic disruption and reduced apoptosis. Conclusively, MTX mitigates T2D-induced myocardial dysfunction by modulating SIRT3-related metabolic and inflammatory signaling pathways, highlighting its potential as a low-cost therapeutic option for diabetes-associated cardiomyopathy.