Targeting DUSP26 to drive cardiac mitochondrial dynamics via FAK-ERK signaling in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a severe cardiac complication of diabetes mellitus, characterized by structural and functional myocardial abnormalities. The molecular mechanisms underlying DCM, particularly the role of dual-specificity phosphatase 26 (DUSP26), remain insufficiently understood. Our study reveals that DUSP26 expression is markedly downregulated in the cardiomyocytes of diabetic db/db mice and under glucolipotoxic stress. Overexpression of DUSP26 in db/db mice significantly improved cardiac function, as demonstrated by enhanced left ventricular ejection fraction and fractional shortening, alongside reduced myocardial fibrosis and hypertrophy. Mitochondrial analysis indicated that DUSP26 overexpression led to increased ATP production, enhanced mitochondrial fusion, and improved structural integrity. In addition, lipid accumulation was reduced, reflecting enhanced metabolic function. We also discovered that DUSP26 is necessary for regulating the focal adhesion kinase (FAK)-extracellular signal-regulated kinase (ERK) pathway, with pharmacological activation of FAK partially offsetting the benefits of DUSP26 overexpression in rescue experiments. These findings underscore the pivotal role of DUSP26 as a potential therapeutic target, highlighting the importance of developing targeted molecular interventions to address diabetic cardiac complications.