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Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function
This study introduces two pan-ERR agonists, SLU-PP-332 and SLU-PP-915, demonstrating their efficacy in improving heart function in a heart failure (HF) model. By activating ERRα and ERRγ, these agonists significantly enhance ejection fraction, reduce fibrosis, and increase survival without affecting cardiac hypertrophy. Their action activates metabolic genes, particularly those involved in fatty acid metabolism and mitochondrial function, leading to normalized metabolic profiles and increased mitochondrial oxidative capacity. ERRγ was identified as the primary mediator of these beneficial effects, offering potential for ERR agonists as novel HF therapeutics.