Sappanone A targets TFEB to promote lysosomal autophagy and attenuate high glucose-induced myocardial injury.

INTRODUCTION Diabetic cardiomyopathy (DCM) involves myocardial injury under hyperglycemia, where impaired autophagy and oxidative stress play critical roles. This study explores whether Sappanone A (a natural compound) alleviates DCM by activating TFEB-mediated lysosomal autophagy.

METHODS In vitro: H9c2 cardiomyocytes were injured with high glucose and treated with Sappanone A. Cell viability (CCK-8), apoptosis (flow cytometry), ROS (DCFHDA), and autophagy markers (LC3-II/I, p62, LAMP1 via WB/qPCR) were assessed. In vivo: STZ-induced DCM mice received Sappanone A (10 mg/kg/day, 8 weeks). Cardiac function (echocardiography), serum ANP/BNP (ELISA), histopathology (H&E/Masson), and autophagy flux (TFEB/LAMP1) were analyzed. TFEB-knockout models and chloroquine (CQ, autophagy inhibitor) validated mechanistic links.

RESULTS Sappanone A dose-dependently enhanced HG-injured cardiomyocyte survival, reduced apoptosis and ROS, while upregulating TFEB nuclear translocatiandlysosomal function.In DCM mice, it improved ejection fraction, reduced fibrosis, and restored autophagic flux.These effects were abolished in TFEB-knockout models or with CQ co-treatment, confirming TFEB-dependent autophagy as the core mechanism.

CONCLUSION Sappanone A protects against DCM by activating TFEB-driven lysosomal autophagy, mitigating oxidative stress, and preserving cardiac function. It represents a novel therapeutic candidate for DCM.