Kojic acid dipalmitate microemulsion ameliorates STZ+HFD-induced metabolic cardiomyopathy via RAGE/Cdc42 pathway

This study investigates the cardioprotective potential of Kojic Acid Dipalmitate Microemulsion (KME) in metabolic cardiomyopathy (MCM). Male Wistar Rats (200-250 g) were used to establish the MCM model by feeding a high-fat diet (HFD) for four weeks, followed by a low dose of streptozotocin (35 mg/kg). The treatment groups were administered different dose ranges (5, 10, and 20 mg/kg) orally for 21 days. Cardiac and metabolic phenotyping was assessed by body and heart weight, body weight-to-heart weight ratio, blood pressure measurements, cTnI, CK-MB, NT-proBNP, insulin levels, metabolic markers (AGE, RAGE, Cdc42), oxidative stress and inflammatory mediators, and histopathological examination. Also, cell viability was evaluated following treatment with doxorubicin and KME, and total protein content was quantified using a protein assay. KME treatment demonstrated dose-dependent cardioprotective effects, attenuated AGE-RAGE-Cdc42 pathway activation, and reduced cardiac hypertrophy index. In the highest concentration of KME (32.3 μM) in vitro assay, KME markedly increased cell survival compared with the doxorubicin control, indicating its protective effect on cellular metabolic activity and protein synthesis under cytotoxic stress. Histopathology confirmed preservation of myocardial architecture with reduced inflammatory cell infiltration, interstitial fibrosis, etc. KME effectively ameliorates cardiac dysfunction, metabolic dysregulation, and pathological cardiac remodelling, making it a promising therapeutic intervention for metabolic cardiomyopathy.