Our study revealed significant upregulation of USP7 in the cardiac microvascular endothelium of HFpEF mice, and EC-specific knockout of USP7 improved HFpEF phenotypes, including cardiac diastolic function, myocardial fibrosis, and exercise tolerance in HFpEF mice, indicating a crucial role of USP7 in the pathogenesis of HFpEF. The gene discussed is USP7; the disease is Myocardial fibrosis.