Estrogen-related receptors (ERRs) belong to the nuclear receptor family and serve as key transcriptional regulators governing myocardial fatty acid oxidation metabolism and mitochondrial biogenesis. ERRs broadly modulate the expression of genes associated with fatty acid uptake, β-oxidation and oxidative phosphorylation in cardiomyocytes, sustaining normal energy supply within the heart. Under pathological heart failure conditions, downregulation of ERR signaling compromises myocardial fatty acid metabolism, disrupts mitochondrial structure and function, creates an energy deficit in the myocardium, and exacerbates cardiac dysfunction. Accordingly, developing small-molecule agonists targeting ERRs to restore myocardial metabolic homeostasis is regarded as a highly promising strategy for heart failure intervention. In this study, guided by structure-based molecular design, researchers developed two Pan-ERR agonist molecules, with SLU-PP-915 as the representative candidate compound.

Molecular Basis of SLU-PP-915: A Structure-Designed Selective Pan-ERR Agonist

SLU-PP-915, CAS No.: 2285432-92-8, is a novel small-molecule Pan-ERR agonist rationally designed by the research team based on receptor crystal structures. The molecule binds to the ligand-binding pocket of ERR receptor proteins and activates ERRα, ERRβ and ERRγ isoforms, achieving broad-spectrum Pan-ERR agonism.

Compared with another analog SLU-PP-332 in the same series, SLU-PP-915 possesses a differentiated chemical scaffold. The two molecules share certain similarities yet exhibit distinctions in molecular interaction details and in vivo pharmacodynamic performance. By activating the ERR signaling axis, SLU-PP-915 upregulates transcription of a large panel of downstream target genes, with predominant regulation of gene sets involved in the myocardial fatty acid metabolic pathway and mitochondrial oxidative phosphorylation (OXPHOS), thereby reshaping the phenotypic profile of myocardial energy metabolism.

In Vivo Animal Models: SLU-PP-915 Ameliorates Pressure Overload-Induced Heart Failure

Researchers established a mouse model of pressure overload heart failure via transverse aortic constriction (TAC) surgery to mimic the clinical pathology of heart failure triggered by elevated pressure load. Following TAC surgery, experimental animals received daily intraperitoneal administration of SLU-PP-915 for intervention.

Cardiac Function and Survival Benefits

Mice in the TAC model group gradually developed reduced cardiac systolic function and decreased ejection fraction. Intervention with SLU-PP-915 significantly improved cardiac systolic function, increased cardiac output, and markedly elevated animal survival rates. Meanwhile, myocardial fibrosis was alleviated, accompanied by downregulated expression of fibrosis-related proteins Nppa and Nppb in cardiac tissue, mitigating pathological myocardial remodeling.

Mitochondrial Structural and Functional Repair

Transmission electron microscopy revealed extensive swelling and fractured cristae, hallmarks of pathological injury, in myocardial mitochondria from TAC model mice. The SLU-PP-915 treatment group demonstrated substantial restoration of mitochondrial ultrastructure, with markedly reduced mitochondrial damage. Functionally, isolated myocardial mitochondria were subjected to functional assays: SLU-PP-915 treatment restored mitochondrial respiratory chain activity and oxygen consumption rate, recovering mitochondrial energy production capacity.

Transcriptomics Uncovers Mechanisms Underlying Metabolic Reprogramming

RNA-seq transcriptome sequencing was performed on primary cardiomyocytes and mouse cardiac tissue. After SLU-PP-915 treatment, numerous genes related to fatty acid metabolism, oxidative phosphorylation and myocardial contraction were significantly upregulated. Enrichment analyses confirmed robust activation of the fatty acid β-oxidation pathway and mitochondrial OXPHOS pathway by the compound. SLU-PP-915 upregulates key ERR downstream target genes such as Pdk4. As a critical regulator governing the switch between glucose and lipid metabolism, Pdk4 shifts myocardial substrate preference toward fatty acid oxidation to compensate for the energy deficit under heart failure conditions.

Further isoform validation experiments verified that the cardioprotective effects of SLU-PP-915 are highly dependent on the ERRγ receptor. Following ERRγ knockout, the compound-mediated improvements in cardiac function and mitochondrial repair were largely abolished, identifying ERRγ as the core target through which SLU-PP-915 exerts myocardial protection.

Key Observation: SLU-PP-915 Improves Heart Failure without Inhibiting Cardiomyocyte Hypertrophy

A notable experimental finding emerged: in the TAC pressure overload animal model and the in vitro phenylephrine (PE)-induced cardiomyocyte hypertrophy model, SLU-PP-915 significantly improved cardiac systolic function and restored mitochondrial energy metabolism, yet did not reverse the hypertrophic phenotype.

Echocardiography in animals showed no meaningful reduction in ventricular wall thickness or cardiac mass index in the SLU-PP-915 treatment group. In in vitro cardiomyocyte assays, drug treatment failed to suppress PE-induced enlargement of cardiomyocyte volume. Mechanistic studies indicated that SLU-PP-915 does not substantially modulate classic cardiomyocyte hypertrophic signaling cascades including ERK1/2 and NFAT.

This points to the therapeutic logic of this candidate molecule: it confers benefits in heart failure primarily by repairing myocardial energy metabolism and rescuing mitochondrial function, rather than directly blocking hypertrophic signaling. Differentiated from conventional anti-hypertrophic agents, it offers an entirely distinct therapeutic paradigm. Even in the presence of persistent cardiac hypertrophy, restoration of energy supply in cardiomyocytes can still improve cardiac function.

Research Value and Industrial Implications: New Candidates Emerge for Metabolism-Targeted Heart Failure Drugs

Current clinically available therapeutics for heart failure predominantly target neuroendocrine inhibitory pathways, while treatment modalities acting on myocardial energy metabolism targets remain limited. Myocardial metabolic reprogramming lies at the heart of heart failure pathology, and the ERR pathway is recognized as a target with strong translational potential. As a novel small-molecule Pan-ERR agonist, SLU-PP-915 complements the toolkit of candidate molecules.

This study demonstrates that reshaping fatty acid metabolism and repairing mitochondria alone can improve cardiac function and increase survival in model animals, even without blocking myocardial hypertrophy. This finding reshapes consensus within the field and broadens perspectives for heart failure drug discovery.

SLU-PP-915 is currently a research-stage tool compound. All available data derive from cellular and animal studies, and human clinical trials have not yet commenced. The molecule provides a lead scaffold for medicinal chemistry and pharmacological research institutions. Extensive follow-up work including druggability optimization, pharmacokinetic profiling and safety evaluation is required, and a lengthy research pipeline remains before clinical application.

This work published in Circulation by the Baylor College of Medicine team describes the Pan-ERR agonist SLU-PP-915. This small molecule activates the ERR nuclear receptor pathway, upregulates myocardial fatty acid oxidation and mitochondrial oxidative phosphorylation, repairs mitochondrial damage in pressure overload heart failure models, improves cardiac systolic function, and prolongs animal survival.

Exerting cardioprotection via “metabolic repair” independent of cardiomyocyte hypertrophy inhibition, this molecule delivers a novel lead compound and theoretical basis for metabolism-targeted drug discovery against heart failure, laying critical groundwork for subsequent small-molecule optimization and target translational research.

Disclaimer: This article is scientific industry news introducing results from published academic research only. SLU-PP-915 is a laboratory research compound that has not undergone human clinical validation and does not constitute promotion of any drug efficacy.