Sappanone A Targets Transcription Factor EB 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 transcription factor EB (TFEB)-mediated lysosomal autophagy.

METHODS

In vitro: H9c2 cardiomyocytes were injured with high glucose (HG) and treated with sappanone A. Cell viability (Cell Counting Kit-8), apoptosis (flow cytometry), reactive oxygen species (ROS; DCFH-DA), and autophagy markers (LC3-II/I, p62, LAMP1 via WB/quantitative real-time PCR) were assessed. In vivo: STZ-induced DCM mice received sappanone A (10 mg/kg/day, 8 weeks). Cardiac function (echocardiography), serum atrial natriuretic peptide/brain natriuretic peptide (enzyme-linked immunosorbent assay), 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 translocation and lysosomal 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.