CTRP9 ameliorates heart failure with preserved ejection fraction by regulating lipid metabolism.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major clinical challenge, with cardiac lipotoxicity emerging as a key driver of disease progression. Despite CTRP9’s role in lipid metabolism and cardioprotective properties, its therapeutic potential in HFpEF remains unexplored. This study aimed to investigate whether CTRP9 ameliorates HFpEF by regulating cardiac lipid metabolism and to identify the underlying molecular mechanisms. METHODS: In the established two-hit HFpEF mouse model (induced by a high-fat diet and L-NAME), the mice were treated with either CTRP9 or saline. Cardiac function was evaluated by echocardiography, while hypertrophy, fibrosis, and lipid accumulation were assessed using histology and molecular assays. Proteomic sequencing was further employed to identify downstream targets of CTRP9. RESULTS: CTRP9 treatment significantly improved diastolic function and attenuated cardiac hypertrophy and fibrosis in HFpEF mice. Myocardial lipid accumulation was substantially reduced, accompanied by enhanced fatty acid oxidation. Proteomic analysis identified GPD1 as a key downstream target upregulated by CTRP9. Cardiac-specific knockdown of GPD1 partly abolished the therapeutic benefits of CTRP9. CONCLUSION: Our data suggest that CTRP9 ameliorates HFpEF through GPD1-mediated regulation of cardiac lipid metabolism, identifying the CTRP9-GPD1 axis as a promising therapeutic target for HFpEF. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07661-2.