Targeting the Src/OXPHOS axis to attenuate myocardial oxidative stress injury in type 2 diabetes.

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of diabetes-associated mortality, with myocardial oxidative stress serving as a pivotal pathological driver of DCM. This study aimed to elucidate the function and mechanism of Src tyrosine kinase in T2DM-associated DCM pathogenesis. MATERIALS AND METHODS: 35 DCM and 72 T2DM patients were enrolled for clinical analysis. In vivo db/db mice and in vitro high glucose-treated H9c2 cardiomyocyte models were established. Src tyrosine kinase activity, oxidative stress levels, mitochondrial function, and oxidative phosphorylation (OXPHOS) profiles were examined, with Src inhibitors (PP2, SrcI1) applied for functional validation. KEY FINDINGS: Clinical study elevated serum Src activity was an independent risk factor for DCM. T2DM models presented enhanced Src activation, severe myocardial oxidative stress, aberrant OXPHOS complex activities, and impaired mitochondrial energy metabolism. Pharmacological Src inhibition markedly ameliorated diabetic myocardial oxidative damage, normalized mitochondrial respiratory function, and recovered ATP production. Notably, the two Src inhibitors exerted distinct regulatory effects on serum antioxidant enzymes, with no impact on myocardial antioxidant enzyme activities. SIGNIFICANCE: Collectively, these findings demonstrate that aberrant Src activation contributes to diabetic myocardial oxidative damage and mitochondrial dysfunction. Targeted Src inhibition protects the diabetic myocardium primarily by restoring OXPHOS homeostasis and improving mitochondrial energy metabolism, rather than modulating myocardial antioxidant enzyme systems.