Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) is a complex multisystem syndrome with a 5-year mortality of 30–60% and limited targeted therapies. Nearly half of patients with HFpEF have metabolic liver disease, supporting a pathogenic liver-heart axis. These conditions share major comorbidities, including obesity, diabetes, and hypertension, as well as overlapping mechanisms such as inflammation, fibrosis, lipid accumulation, and oxidative stress. Chemerin, a hepatokine produced by the liver and adipose tissue, has emerged as a promising mediator of liver-heart crosstalk. By signaling through the G protein-coupled receptor CMKLR1 on macrophages, vascular cells, and cardiomyocytes, chemerin regulates immune cell trafficking, inflammatory signaling, and tissue remodeling.
Hypothesis: We hypothesized that chemerin signaling drives liver-heart crosstalk in HFpEF by promoting NLRP3 inflammasome activation and lipid accumulation.
Aim: To define the mechanistic role of chemerin signaling in hepatic-cardiac inflammation, fibrosis, and metabolic injury, and to determine whether CMKLR1 antagonism attenuates pathological remodeling.
Methods: Chemerin expression was evaluated in blood, liver, and heart tissues from HFpEF mice (n=6). Mechanistic studies were performed in induced pluripotent stem cell-derived cardiomyocytes treated with the CMKLR1 antagonist α-NETA (5μM, 24 h). NLRP3 inflammasome activation, fibrosis-associated signaling, and lipid accumulation were assessed.
Results: Chemerin signaling was significantly increased in plasma (p<0.0001), liver (p<0.01), and heart tissues (p<0.05) from HFpEF mice. This increase was associated with enhanced NLRP3 inflammasome activation. In cardiomyocytes, α-NETA reduced inflammasome activation, fibrosis, and lipid accumulation.
Conclusion: Chemerin is a potential mechanistic link between hepatic metabolic injury and cardiac dysfunction in HFpEF. Targeting CMKLR1 may suppress inflammasome-driven metabolic and fibrotic remodeling.