Thrombospondin 1 aggravates cardiac remodeling in heart failure with preserved ejection fraction by inhibiting mitophagy

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases, but its underlying mechanisms remain unclear. Mitochondrial dysfunction and defective mitophagy are increasingly recognized as central features of HFpEF. Thrombospondin 1 (Thbs1), a matricellular protein involved in cardiovascular remodeling, has not been explored in this context. Here, we show that <i>Thbs1</i> expression is elevated in HFpEF myocardium and that <i>Thbs1</i> aggravates cardiac dysfunction by inhibiting mitophagy. In a "two-hit" HFpEF mouse model induced by high-fat diet and L-NAME, AAV9-mediated <i>Thbs1</i> knockdown improved diastolic function, reduced fibrosis and inflammation, and mitigated PI3K/Akt/mTOR pathway activation revealed by transcriptomic and proteomic profiling. Mechanistically, <i>Thbs1</i> silencing restored autophagic flux, enhanced mitochondrial clearance, and preserved mitochondrial homeostasis in cardiomyocytes. These findings identify <i>Thbs1</i> as a key suppressor of mitophagy in HFpEF and a potential therapeutic target for this prevalent condition.