Colchicine Modulates Cardiac Autophagy and Attenuates Pathophysiology in a Heart Failure Murine Model with Preserved Ejection Fraction.

INTRODUCTION: The study aims to explore the protective effect of colchicine on heart failure with preserved ejection fraction (HFpEF) and its underlying mechanism, with a focus on the regulatory role of the mTOR signaling pathway. METHODS: Thirty C57BL/6J mice were used to establish the HFpEF model and were randomized into three groups: control, model, and colchicine-treated groups. Colchicine was administered for 6 weeks. Cardiac function was evaluated by echocardiography, exercise capacity testing, and hemodynamic measurements. Western blot, real-time quantitative PCR, and histological analyses were performed to assess mTOR expression, autophagy-related proteins, myocardial fibrosis, and inflammatory responses in cardiac tissue. The potential interaction between colchicine and mTOR was analyzed by molecular docking simulation. Notably, molecular docking was performed once, not redundantly. RESULTS: The mice in the model group showed myocardial fibrosis, inflammatory responses, and mTOR overactivation. Colchicine treatment significantly reduced systolic and diastolic pressure in the model group, improved cardiac function, modulated mTOR- and autophagy-related gene expression, and attenuated myocardial fibrosis and inflammatory factor release. DISCUSSION: The findings confirm that colchicine ameliorates key pathological features of HFpEF, including diastolic dysfunction, fibrosis, and inflammation. Mechanistically, this protective effect is associated with suppression of mTOR overactivation and normalization of autophagic activity, as supported by molecular docking and expression data. However, the causal relationship between mTOR inhibition, autophagy regulation, and functional improvement remains to be validated using genetic or pharmacological modulators. These results support colchicine as a promising therapeutic agent targeting the mTOR-autophagy axis in HFpEF. CONCLUSION: Colchicine may modulate mTOR signaling, regulate autophagy, reduce inflammation, and alleviate myocardial fibrosis in HFpEF.