Animal only
This systematic review examines the preclinical evidence for pharmacological activation of estrogen-related receptors (ERRα/β/γ) as a strategy to mimic the beneficial effects of exercise. The authors focused on synthetic pan-ERR agonists, particularly SLU-PP-332 and SLU-PP-915, reviewing experimental literature published between 2020 and 2024 from animal and cell-based models. The review found that these compounds appear to induce a gene expression program resembling that of acute aerobic exercise, dependent on ERRα, including activation of genes such as Ddit4 and Slc25a25. In preclinical obesity models, pan-ERR agonists were associated with enhanced fatty acid oxidation, increased oxidative-glycolytic (type IIa) muscle fiber composition, improved endurance capacity, reduced adiposity, better glycemic control, and increased basal energy expenditure, all without apparent toxicity signals. The compounds also showed potential to restore mitochondrial function and reduce inflammation in aging kidney models. The authors conclude that ERR activation is a promising exercise-mimetic strategy but explicitly acknowledge that no human clinical trials have been conducted, making translation to clinical practice premature. This represents a major limitation of the current evidence base.
Revista medica de Chile · Feb 2026DOI ↗ Animal only
This preclinical study characterizes SLU-PP-915, a novel orally bioavailable pan-agonist of estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) — orphan nuclear receptors that regulate mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. The researchers compared SLU-PP-915 to a previously developed ERR pan-agonist, SLU-PP-332, which lacks oral bioavailability. In mouse models, both compounds similarly enhanced aerobic exercise performance (measured by running distance and duration) when administered intraperitoneally, and SLU-PP-915 maintained comparable efficacy via oral administration when adjusted for systemic exposure. Both compounds strongly induced expression of Ddit4, a gene upregulated by acute aerobic exercise, at levels matching or exceeding those produced by treadmill running, depending on the muscle group examined. Notably, SLU-PP-915 appeared to synergize with exercise training to further enhance Ddit4 and mitochondrial gene expression. The authors propose that orally active ERR agonists could have therapeutic relevance for metabolic disorders, cardiovascular disease, and muscle pathologies. Key limitations include exclusive use of animal models, with no human data reported, and the need for long-term safety and efficacy evaluation.
The Journal of pharmacology and experimental therapeutics · Dec 2025DOI ↗ Animal only
This preclinical study investigated SLU-PP-332, a synthetic agonist targeting estrogen-related receptors (ERRα, ERRβ, and ERRγ), as a potential pharmacological "exercise mimetic" for treating obesity and metabolic syndrome. Researchers administered the compound to two mouse models — diet-induced obese mice and genetically obese (ob/ob) mice — and measured a range of metabolic outcomes. The study found that SLU-PP-332 administration was associated with increased whole-body energy expenditure and enhanced fatty acid oxidation, effects the authors liken to those induced by aerobic exercise. These changes were accompanied by reductions in fat mass accumulation. The compound also appeared to improve insulin sensitivity in the metabolic syndrome models. The study's primary limitation is that all experiments were conducted exclusively in mouse models, meaning the findings cannot be directly extrapolated to humans. Differences in ERR biology, pharmacokinetics, and disease physiology between rodents and humans represent significant translational barriers. The authors conclude that pharmacological ERR activation warrants further investigation as a potential strategy for metabolic disease treatment.
The Journal of pharmacology and experimental therapeutics · Jan 2024DOI ↗ Animal only
This study investigated whether activating estrogen-related receptors (ERRα and ERRγ) — key regulators of cardiac metabolism — could treat heart failure (HF). Researchers designed two novel pan-ERR agonist compounds, SLU-PP-332 and SLU-PP-915, using structure-based drug design, and tested them in a mouse model of pressure overload-induced HF. Both compounds significantly improved ejection fraction, reduced cardiac fibrosis, and increased survival in mice without causing additional cardiac hypertrophy. Multi-omics analyses (RNA sequencing and metabolomics) revealed that ERR agonists broadly activated metabolic gene programs — particularly those governing fatty acid oxidation and mitochondrial function — and substantially normalized disrupted metabolic profiles in failing hearts. In vitro and in vivo genetic dependency experiments identified ERRγ as the primary mediator of these cardioprotective effects and confirmed target specificity. The study also found that ERR agonism downregulated cell cycle and developmental pathways, partly via the transcription factor E2F1. Limitations include that all in vivo work was conducted in mice, and no human data were presented. The authors conclude that ERR agonists represent a promising pharmacologic strategy for HF, warranting further development.
Circulation · Nov 2023DOI ↗ Animal only
This mouse study investigated the role of estrogen-related receptors (ERRs) in age-related kidney decline, focusing on mitochondrial dysfunction and inflammation as key mechanisms. The researchers first observed that ERR expression was reduced in both aging human and mouse kidneys, and that lifelong caloric restriction (CR) preserved ERR levels in mice. They then treated 21-month-old mice (equivalent to elderly) for 8 weeks with a pan-ERR agonist (SLU-PP-332) or for 3 weeks with a STING pathway inhibitor (C-176). The ERR agonist treatment reversed age-associated increases in albuminuria (a marker of kidney damage), podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, acting through the cGAS-STING and STAT3 signaling pathways — effects resembling those of caloric restriction. STING inhibition reduced inflammatory cytokines and the senescence marker p21, but also unexpectedly restored mitochondrial pathway components (PGC-1α, ERRα, mitochondrial complexes, MCAD). The study identifies ERRs as potential CR mimetics and highlights the cGAS-STING pathway as a link between mitochondrial dysfunction and renal inflammation in aging. Key limitations include reliance on animal models, short treatment durations, and the absence of human interventional data.
The American journal of pathology · Sep 2023DOI ↗ Animal only
This study identified SLU-PP-332, a synthetic pan-agonist targeting all three estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ), with the highest potency for ERRα. Researchers first characterized the compound's pharmacokinetic properties to confirm it could be used as an in vivo tool. In cultured skeletal muscle cells, SLU-PP-332 was shown to increase mitochondrial function and cellular respiration. In mouse experiments, administration of SLU-PP-332 increased type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. The study also demonstrated that the compound induced a genetic program closely resembling an acute aerobic exercise response, and that this effect was ERRα-dependent — mice lacking ERRα did not show the same enhancement in exercise endurance. The authors propose that targeting ERRα may be a viable strategy for developing exercise mimetics useful in treating metabolic disorders and age-related muscle decline. Key limitations include that all in vivo experiments were conducted in mice, no human data were generated, and the long-term safety and efficacy of SLU-PP-332 remain untested.
ACS chemical biology · Mar 2023DOI ↗ Animal onlyPreprint
This study investigated whether a synthetic small-molecule agonist of the orphan nuclear receptor ERRα (estrogen receptor-related receptor alpha), called SLU-PP-332, could mimic the genetic and physiological effects of aerobic exercise in skeletal muscle. Researchers first used cell-based assays to confirm that SLU-PP-332 activates ERRα and found it triggered an acute aerobic exercise-associated gene expression program in skeletal muscle cells in an ERRα-dependent manner. In cell culture experiments, the compound increased mitochondrial function and cellular respiration. When administered to mice, SLU-PP-332 was reported to increase the proportion of type IIa oxidative skeletal muscle fibers and improve exercise endurance capacity. The authors propose that ERRα is a viable pharmacological target for developing "exercise mimetic" compounds, which could potentially help treat metabolic disorders and age-related muscle decline. Key limitations include the preclinical (mouse and cell-based) nature of all findings, the absence of human data, and the preprint status of the paper, meaning it had not yet undergone formal peer review at the time of reporting. No conclusions about human efficacy or safety can be drawn from this work alone.
Unknown journal · Oct 2022DOI ↗ Animal onlyPreprint
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.
Unknown journal · Feb 2022DOI ↗