Novel ERR pan-agonists ameliorate heart failure through boosting cardiac fatty acid metabolism and mitochondrial function
This study investigated whether pharmacological activation of estrogen-related receptors (ERRα and ERRγ) could serve as a therapeutic strategy for heart failure. Using structure-based drug design, researchers developed two novel synthetic pan-ERR agonists — SLU-PP-332 and SLU-PP-915 — and tested them in a mouse model of pressure overload-induced heart failure. Both compounds significantly improved cardiac ejection fraction and reduced fibrosis without affecting cardiac hypertrophy. Mechanistic analyses revealed that ERR agonists broadly activated metabolic gene programs, particularly those governing fatty acid oxidation and mitochondrial function, with ERRγ identified as the primary mediator. Metabolomics profiling showed that SLU-PP-915 normalized disrupted fatty acid/lipid and TCA cycle/oxidative phosphorylation metabolite profiles in failing mouse hearts. The agonists also induced autophagy in cardiomyocytes and downregulated cell cycle and developmental pathways, partly via suppression of the transcription factor E2F1. The study is limited to preclinical mouse models with no human data, and the long-term safety profile of these compounds remains uncharacterized. The authors conclude that these findings provide direct pharmacological evidence supporting further development of ERR agonists as heart failure therapeutics.
Why this grade: All experimental findings come from mouse pressure-overload models and cell-based assays, with no human subjects or clinical data reported; additionally, the work is a preprint and has not yet undergone peer review.
Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for heart failure. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effect in vivo . Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad-spectrum of metabolic genes were transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function, which were mainly mediated by ERRγ. Metabolomics analysis showed significant normalization of metabolic profiles in fatty acid/lipid and TCA/OXPHOS metabolites by 915 in the mouse heart with 6-week pressure overload. Autophagy was also induced by ERR agonists in cardiomycoyte. On the other hand, ERR agonism led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo . Our results provided direct pharmacological evidence supporting the further development of ERR agonists as novel heart failure therapeutics in vivo .
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