Inside every cell there are switches called ERRs (estrogen-related receptors) that control genes for burning fat and building the tiny energy factories (mitochondria) that muscle needs to perform. Hard aerobic exercise turns these switches on naturally. Researchers at Saint Louis University built SLU-PP-332 to turn on the same switches directly, without a workout - which is why it's nicknamed an "exercise mimetic" or exercise in a pill. Since it was first described in 2023, it has been tested in mouse models of obesity, heart failure, and kidney aging, plus a small experiment on human muscle cells removed during hip surgery. No published study has given this compound to a person and measured what happens to their body. Chemists are already working on next-generation, more drug-like versions (including one called SLU-PP-915 that can be taken by mouth), and anti-doping labs have started building tests to detect it, because regulators expect it could eventually be misused by athletes.
How strong is the evidence?
Of the 12 papers on file, the great majority are mouse experiments or lab (cell-based) work done by one core research group and their collaborators. There is exactly one study that used tissue from real people - human muscle cells taken from women having hip surgery, treated with the compound afterward in a lab dish, not given to the women themselves. Two other papers examine how the human liver breaks the drug down using liver tissue in test tubes, which tells us about metabolism but nothing about whether the drug works or is safe in a living person. A 2026 review of the whole field states plainly that clinical trials are still needed to confirm this works or is safe in humans. Bottom line: this is early-stage animal and lab science, not a proven human therapy.
Uses
What people use it for
Mimicking exercise's metabolic effects
Animal / labThis is the core idea behind the compound: give it to an animal and its muscles respond as if it had just exercised, building more of the oxygen-burning muscle fibers used in endurance activity and running longer on a treadmill. Only shown in mice so far.
Obesity and metabolic syndrome research
Animal / labIn obese mice, the compound lowered body fat, boosted calorie burning, and improved how well the body handles blood sugar. Researchers see it as a potential future treatment for obesity and metabolic syndrome, but this is mouse data only.
Heart failure research
Animal / labIn mice with a surgically induced form of heart failure, the compound (and a close relative) improved how well the heart pumped and helped the animals survive longer. Being studied as a possible future heart-failure treatment strategy, not a therapy tested in heart patients yet.
Kidney aging research
Animal / labIn old mice, an 8-week course of the compound reversed several signs of age-related kidney decline, including protein leaking into the urine and loss of specialized filtering cells. This mirrors what calorie restriction does in the same animals.
Age-related muscle loss and inactivity research
Animal / labMuscle cells taken from inactive older women and treated with the compound in a lab dish showed molecular signs of healthier, more active muscle and formed new muscle fibers more readily. This used real human tissue, but it was cells in a dish, not people taking the drug.
Potential benefits
What it may help with
Triggered an exercise-like response and boosted endurance in mice
Animal / labA single dose program increased the type of muscle fiber built for endurance, ramped up energy production inside muscle cells, and let mice run further and longer than untreated mice, all without them doing any extra activity.
Studies:36988910Reduced body fat and improved blood sugar control in obese mice
Animal / labIn mice with diet-induced obesity or a genetic obesity condition, the compound increased calorie burning and fat burning, shrank fat mass, and improved the body's response to insulin - the same pattern seen after real exercise.
Studies:37739806Protected the heart in a heart-failure mouse model
Animal / labIn mice with heart failure caused by high pressure in the heart, the compound (and a related molecule) improved the heart's pumping ability, reduced scarring, and helped the animals live longer, mainly by getting heart muscle cells to burn fat and use oxygen more efficiently.
Studies:37961903Reversed signs of kidney aging in old mice
Animal / labAged mice treated for 8 weeks showed less protein leaking into the urine, better-preserved kidney filtering cells, healthier energy-producing structures inside cells, and lower inflammation - changes that matched what happens with lifelong calorie restriction. Follow-up genetic work in mice supports the same biological pathway.
Improved markers of muscle health in cells from inactive, older women
Animal / labMuscle cells taken during hip surgery from inactive women were treated with the compound in a lab dish. Treated cells showed lower cell stress and aging markers, higher levels of proteins linked to healthy mitochondria and muscle repair, and formed new muscle fibers more easily. This is real human-derived tissue, but tested outside the body, not as a treatment given to a person.
Studies:40692696
What to watch for
Side effects & risks
- Moderate
No human safety data exists at all
Because no study has given this compound to a living person, there is no established side-effect profile for humans. A 2026 review of the whole research field explicitly says clinical trials are still needed to confirm safety. Treat anything sold as this compound as an unstudied, unapproved substance.
- Mild
The liver breaks it down into more than 20 different byproducts, and their effects are unknown
Lab studies using human liver tissue found the body converts this compound into over 20 breakdown products through oxidation and other chemical changes. These studies were done purely to help anti-doping labs detect the drug - they don't tell us whether any of these breakdown products cause problems in a real person over time.
Dosing
Dosing — what studies used
There is no established human dose, because this compound has never been tested in people. Everything known about dosing comes from mice. Across the mouse studies, researchers gave the compound by injection (it doesn't absorb well when swallowed, which is a key reason a newer, orally active cousin compound was later developed). Exact milligram-per-kilogram amounts and dosing schedules are not disclosed in the published abstracts reviewed here; the clearest detail available is that one aging-kidney study ran an 8-week treatment course. Anything below describes what researchers did in animals, not a protocol a person could safely copy.
Exercise capacity and metabolic studies in mice
Animal studyNot disclosed in the published abstracts on file
Repeated dosing during the study period (exact schedule not detailed in the abstracts) · Varies by study; one aging-kidney study used an 8-week course in 21-month-old mice · Injection into the abdominal cavity (intraperitoneal), since this version of the compound is not well absorbed when taken by mouth
This reflects research conditions used to study biology in mice, not a usable human protocol. No published study has established a human dose, schedule, or duration.
A chemically different, orally active relative called SLU-PP-915 has since been developed specifically because SLU-PP-332 is not well absorbed when swallowed - a sign that dosing SLU-PP-332 itself realistically means injection, in a research setting only.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Cells have built-in switches called ERRs (short for estrogen-related receptors) that control genes for burning fat and building mitochondria - the tiny structures inside cells that produce energy. Hard aerobic exercise flips these switches on, which is part of why regular training makes muscle more efficient at burning fat and using oxygen. SLU-PP-332 is designed to flip the same switches on directly, tricking muscle, fat, heart, and kidney cells into behaving as if the body were exercising, even when it isn't. Of the three ERR switches (called ERRα, ERRβ, and ERRγ), this compound turns on all three but has its strongest effect on ERRα, which mouse studies show is the one most responsible for the exercise-like boost in stamina.
Who should avoid it
- Anyone considering it as a substitute for approved treatments for obesity, heart failure, diabetes, or kidney disease - it is not an approved medicine and has not been proven to work or be safe in people
- Pregnant or breastfeeding people - no safety data exists in any species for this situation
- People with existing heart, kidney, or liver conditions - all promising results come from animal models, not human patients, so real-world safety in sick humans is unknown
- Competitive athletes in tested sports - anti-doping laboratories are already developing detection methods for this compound because of its exercise-mimicking effects
- Children and teens - no safety data exists in any age group
- Anyone buying it as an unregulated "research chemical" - there is no quality control, dosing standard, or safety monitoring for products sold this way
Interactions to know
- Not studied - no drug interaction data exists in people, because this compound has never been given to a person alongside other medications.
The papers that matter most
Key studies
The original paper describing SLU-PP-332: it increased mitochondrial function in muscle cells and, in mice, increased endurance-type muscle fibers and boosted exercise endurance through the ERRα switch specifically.
Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity
In obese mice, the compound mimicked exercise's metabolic benefits - more calorie and fat burning, less fat mass, and better insulin sensitivity - positioning it as a potential future obesity/metabolic syndrome treatment.
A Synthetic ERR Agonist Alleviates Metabolic Syndrome
In mice with pressure-induced heart failure, the compound improved heart pumping ability, reduced scarring, and increased survival, mainly by restoring the heart's ability to burn fat for fuel.
Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function
An 8-week course reversed several markers of age-related kidney decline in old mice, matching the effect of lifelong calorie restriction - one of the more mechanistically detailed papers in the set.
Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney
The closest thing to human data in this evidence set: muscle cells taken from inactive older women showed healthier mitochondrial and muscle-repair markers after treatment in a dish. Still cell-based, not a treatment given to a person.
Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study
A 2026 review summarizing all the preclinical evidence for SLU-PP-332 and its cousin compound, concluding the science is promising but explicitly stating that clinical trials in humans are still needed to confirm efficacy and safety.
Pharmacological Activation of ERRα/β/γ as an Exercise Mimetic: Potential Therapeutic Applications
Bottom line
SLU-PP-332 has a genuinely interesting and growing body of mouse research behind it - for obesity, heart failure, kidney aging, and exercise capacity - all pointing the same direction, plus one intriguing look at human muscle cells in a dish. But no one has ever given it to a person and measured what happens, so there is no human proof it works and no human safety data at all. This is promising early-stage science, not something to try on yourself.
Research papers
Studies we have on file for SLU-PP-332. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
12 papers
A Synthetic ERR Agonist Alleviates Metabolic Syndrome.
Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.
Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity.
Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the identification of a synthetic ERR pan agonist, SLU-PP-332, that targets all three ERRs but has the highest potency for ERRα. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an in vivo chemical tool. SLU-PP-332 increases mitochondrial function and cellular respiration in a skeletal muscle cell line. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. We also observed that SLU-PP-332 induced an ERRα-specific acute aerobic exercise genetic program, and the ERRα activation was critical for enhancing exercise endurance in mice. These data indicate the feasibility of targeting ERRα for the development of compounds that act as exercise mimetics that may be effective in the treatment of numerous metabolic disorders and to improve muscle function in the aging.
Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.
Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available. Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity. Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes. ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.
An orally active estrogen receptor-related receptor agonist, SLU-PP-915, enhances aerobic exercise capacity.
Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs are essential for skeletal muscle adaptation to aerobic exercise and represent promising targets for exercise mimetic therapeutics. We previously developed an ERR pan-agonist, SLU-PP-332 (332), which improves aerobic performance in mice but lacks oral bioavailability. Here, we characterize SLU-PP-915 (915), a chemically distinct ERR pan-agonist that is orally bioavailable and exhibits potent in vivo exercise mimetic activity. Compound 915 enhances aerobic exercise performance (distance and duration) to a similar extent as 332 when administered intraperitoneally and maintains comparable efficacy when administered orally, adjusted for systemic exposure. Both compounds robustly induce the expression of DNA damage-inducible transcript 4 (Ddit4), a gene induced by acute aerobic exercise, with levels matching or exceeding levels induced by treadmill running, depending on the muscle examined. Notably, 915 synergizes with exercise training to further enhance Ddit4 and mitochondrial gene expression. These findings position orally active ERR agonists such as 915 as promising agents for the treatment of metabolic disorders (eg, obesity, type 2 diabetes, and metabolic disease-associated steatohepatitis), cardiovascular disease (heart failure), and muscle-related pathologies, including sarcopenia and muscular dystrophies. SLU-PP-915 offers a valuable chemical tool for exploring the chronic therapeutic potential of ERR activation. SIGNIFICANCE STATEMENT: The nuclear receptor estrogen receptor-related receptor plays an important role in driving the physiological adaptations to exercise. The article describes the ability of a pan-estrogen receptor-related receptor agonist SLU-PP-915, which also displays oral bioavailability, to enhance exercise capacity.
Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney.
A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging, per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. This study examined the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation. The ERRs were decreased in both aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). A pan-ERR agonist, SLU-PP-332, was used to treat 21-month-old mice for 8 weeks. In addition, 21-month-old mice were treated with a stimulator of interferon genes (STING) inhibitor, C-176, for 3 weeks. Remarkably, similar to CR, an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, via the cyclic GMP-AMP synthase-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker, p21/cyclin dependent kinase inhibitor 1A (Cdkn1a), but also unexpectedly reversed the age-related decreases in PPARG coactivator (PGC)-1α, ERRα, mitochondrial complexes, and medium chain acyl coenzyme A dehydrogenase (MCAD) expression. These studies identified ERRs as CR mimetics and as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.
In Vitro Metabolism and Analytical Characterization of SLU-PP-332 and SLU-PP-915: Novel Pan-ERR Agonists With Doping Potential.
Estrogen-related receptor (ERR) agonists such as the drug candidates SLU-PP-332 and SLU-PP-915 are currently being investigated as exercise mimetics, given their ability to trigger human physiological processes similar to those initiated by actual physical activity. This capability prompted the consideration of these compounds as drugs potentially relevant for sports drug testing programs. The two pan-ERR agonists SLU-PP-332 and SLU-PP-915 were characterized using liquid chromatography-high resolution (tandem) mass spectrometry (LC-HRMS/MS). Furthermore, the in vitro metabolic transformation products of both compounds prepared by means of human liver S9 fraction (S9 fraction) and human liver microsomes (HLMs) were analyzed. In addition, selected metabolites of SLU-PP-915 were synthesized and their structures were analyzed by nuclear magnetic resonance (NMR) spectroscopy. A total of nine metabolites were identified for SLU-PP-332, consisting of six Phase-I metabolites and three Phase-II conjugates. Conversely, the analysis of SLU-PP-915 yielded only Phase-I transformation products, with a total of seven metabolites identified. In both cases, an in-depth structural elucidation was conducted to obtain a comprehensive overview of the detected metabolites. Furthermore, three metabolites of SLU-PP-915 were confirmed through chemical synthesis and NMR. The results obtained in this study gave an in-depth view into the analysis and in vitro metabolism of the newly developed pan-ERR agonists SLU-PP-332 and SLU-PP-915. This may help to uncover the illicit use of these novel compounds as potential performance-enhancing substances.
Analysis and Identification of In Vitro Metabolites of Exercise Mimetic SLU-PP-332 ERRα/β/γ Agonist for Doping-Control Purposes.
Exercise mimetics mimic physical activity and prevent development and progression of chronic metabolic diseases, including obesity and Type 2 diabetes. The World Anti-Doping Agency (WADA) prohibits the use of exercise mimetics and metabolic modulators in sports. SLU-PP-332 is a small, synthetic ERRα/β/γ agonist recently developed using a rational drug design approach. SLU-PP-332 has been shown to increase oxidative muscle fibers, fatty acid oxidation, and enhance exercise endurance. In mouse models of metabolic syndrome, it increased energy expenditure and insulin sensitivity and conferred cardiac protection against pressure overload-induced heart failure by transcriptionally activating a wide spectrum of metabolic genes involved in fatty acid metabolism and mitochondrial function. The identification of metabolites of this emerging therapeutic molecule is a critical step towards detecting its misuse. The aim of the study was identification of Phase I and II metabolites generated in vitro using pooled human liver S9 fractions. Metabolites were analyzed using liquid chromatography-high-resolution mass spectrometry (LC-MS/HRMS). Five monohydroxylated (M1-M5), three dihydroxylated (M6-M8), and four reduced dihydroxylated metabolites (M9-M12) were identified. Metabolites M13 and M19 showed direct glucuronidation and sulfation of the parent compound, respectively. Metabolites M14-M18 and M20-M22 showed glucuronidation and sulfation with hydroxylation of the naphthalene or phenolic rings, respectively. M1, M7, M9, M10, M13, M14, M19, and M20 were the most abundant of the 22 metabolites and potentially useful for doping-control purposes. Further studies are necessary to fully elucidate the structures of the metabolites.
Chemical optimization of the exercise mimetic SLU-PP-332 enables insight into estrogen-related receptor signaling.
Estrogen-related receptors (ERRs) are master regulators of mitochondrial metabolism and exercise-responsive transcription, yet only a limited number of synthetic agonists with suitable potency and drug-like properties have been reported. SLU-PP-332 is a well-established exercise mimetic and widely used chemical probe for ERR activation; however, the structural features governing its potency, efficacy, selectivity, and drug-like properties have not been systematically elucidated. Here, we report the first comprehensive structure-activity relationship (SAR) analysis of the SLU-PP-332 scaffold, integrating chemical synthesis, cell-based functional assays, downstream gene-expression profiling, and computational modeling. Through iterative modification of core pharmacophoric elements, we identify key structural determinants that control ERRα and ERRγ agonism, transcriptional efficacy, ligand efficiency, and physicochemical properties. While SLU-PP-332 remains a strong benchmark for ERR activation, several analogues achieve comparable or context-dependent transcriptional responses while exhibiting improved ligand efficiency, solubility, or metabolic stability. Computational docking and molecular dynamics simulations reveal how subtle structural modifications influence ERR engagement and signaling outcomes. Together, this work defines design principles for tuning ERR agonism and provides a foundational SAR roadmap for the rational development of next-generation ERR agonists and exercise-mimetic therapeutics.
Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study.
Estrogen-related receptors has been suggested as a potential therapeutic target to counteract muscle decline associated with aging or inactivity, being known to regulate mitochondrial function and cellular respiration by up-regulating key factors in muscle responses to exercise. This study aimed to evaluate the targeting of ERRs in myoblasts isolated from the skeletal muscle of inactive women by assessing the metabolic and expression changes associated with its activation. Twenty women undergoing hip arthroplasty for coxarthrosis were enrolled and divided into an active group (n = 10) and an inactive group (n = 10) based on self-reported physical activity. During surgery, muscle biopsies were taken for histological and western blotting analysis, measuring the expression levels of NADPH oxidase 4 (NOX4), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), estrogen related receptor alpha (ERRα), and fibronectin type III domain-containing protein 5 (FNDC5). Primary cultures of myoblasts were set up from the muscle tissue of inactive women and treated with the ERRs agonist, SLU-PP-332, for subsequent qualitative and quantitative investigations. In addition, myoblasts were differentiated into myotubes for 15 days, and the success of differentiation was evaluated by immunofluorescence analysis. Clinical and instrumental evaluation showed less functional limitation, higher handgrip strength values, and significantly reduced visual analogue scale scores in active subjects, in association with a significant increase in muscle fiber diameter. In addition, significantly higher expression of NOX4, concomitant with reduced levels of SIRT1, PGC-1α, ERRα, and FNDC5, was detected in the muscle tissue of inactive women. Interestingly, SLU-PP-332 treatment promoted down-regulation of NOX4 and upregulation of SIRT1, PGC-1α, ERRα, FNDC5, Akt, and B-cell lymphoma 2 (Bcl-2) in myoblasts, reducing cytotoxicity, oxidative stress, and senescence, as well as increasing levels of reduced glutathione. Furthermore, SLU-PP-332 treatment promoted abundant myotube formation, positively influencing cell differentiation. Targeting ERRs could represent a promising therapeutic strategy to counteract muscle atrophy in elderly and sedentary subjects. However, further studies are needed to clarify the molecular mechanisms involved and explore the impact of ERRs activation on muscle metabolism.
[Pharmacological Activation of ERRα/β/γ as an Exercise Mimetic: Potential Therapeutic Applications].
Physical inactivity contributes to the development of chronic diseases. Activation of orphan nuclear receptors estrogen-related receptors (ERRα/β/γ) has emerged as a molecular strategy to mimic exercise-induced benefits. To systematically review the current evidence on the physiological, molecular, and clinical effects of synthetic pan-ERR agonists, especially SLU-PP-332 and SLU-PP-915, in preclinical models and their potential as exercise mimetics. A systematic review of scientific literature from 2020 to 2024 was conducted, including experimental studies in animals and cell models. Molecular mechanisms, effects on energy metabolism, muscle function, renal aging, and metabolic syndrome were analyzed. Pan-ERR agonists induce a gene expression program like acute aerobic exercise, dependent on ERRα, including activation of Ddit4 and Slc25a25. They enhance fatty acid oxidation, increase type IIa muscle fibers (oxidative-glycolytic, with mixed substrate utilization including fatty acids and glucose), and improve endurance. SLU-PP-332 and SLU-PP-915 reduce adiposity, improve glycemic control, and increase basal energy expenditure in obesity models, without evident toxicity. Additionally, they restore mitochondrial function and reduce inflammation in aging kidneys. Pharmacological activation of ERRα/β/γ is a promising strategy as an exercise mimetic, with potential therapeutic applications in metabolic diseases, aging, and muscle-related conditions. Clinical trials are needed to confirm their efficacy and safety in humans.
ERRγ deletion in podocytes accelerates aging related kidney disease.
We have recently demonstrated that treatment of aged mice with a pan-ERR agonist reverses age-related increase in urinary albumin, decrease in podocyte density, impaired mitochondrial function, and inflammation. The contribution of individual isoforms of ERRs however has not been determined. Since the aging kidney showed a possible compensatory increased expression of ERRγ in the podocytes, in the face of decreased ERRα expression, in the present study we aimed to determine the role of ERRγ in aging podocyte. To this end, we cross bred ERRγ floxed mice with podocin-Cre mice to achieve a podocyte-specific ERRγ deletion. While these mice at 3 months of age showed no effect on albuminuria compared to the wild type, when the mice were aged to 21 months of age, there was a significant increase in albuminuria and decrease in podocyte density. Furthermore, we found that the podocyte deletion of ERRγ primarily targeted the expression of mitochondrial biogenesis regulator PGC-1α, and mitochondrial fatty acid oxidation enzymes CPT1a and MCAD in the kidney. Electron Microscopy (EM) revealed thickened glomerular basement membrane and diffuse podocyte foot process effacement, as well as severe mitochondrial damage including cristae abnormalities, fragmentation, and changes indicative of altered fusion and fission dynamics. Fluorescence Lifetime Imaging Microscopy (FLIM) to determine NADH and FAD lifetimes indicate a metabolic shift from mitochondrial oxidative phosphorylation towards glycolysis, and decrease in mitochondrial redox capacity. Considering a significantly decreased expression of ERRα in aging podocytes plus its traditional role in mitochondrial function, these studies using podocyte ERRγ deletion suggested an overlapping mechanism for ERRα/ERRγ to act as modulators of age-related mitochondrial dysfunction and age-related kidney disease.
ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease.
Parkinson's disease is assumed to be caused by mitochondrial dysfunction in the affected dopaminergic neurons in the brain. We have recently created small chemicals, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption. By contrast, agonistic ligands of ERRs (estrogen receptor-related receptors) are expected to raise cellular ATP levels via enhancing ATP production. Here, we show that esculetin functions as an ERR agonist, and its addition to culture media enhances glycolysis and mitochondrial respiration, leading to elevated cellular ATP levels. Subsequently, we show the neuroprotective efficacies of KUSs, esculetin, and GSK4716 (an ERRγ agonist) against cell death in Parkinson's disease models. In the surviving neurons, ATP levels and expression levels of α-synuclein and CHOP (an ER stress-mediated cell death executor) were all rectified. We propose that maintenance of ATP levels, by inhibiting ATP consumption or enhancing ATP production, or both, would be a promising therapeutic strategy for Parkinson's disease.
Quick links (PubMed)
- PMID 37739806 — 2024 · A Synthetic ERR Agonist Alleviates Metabolic Syndrome.
- PMID 36988910 — 2023 · Synthetic ERRα/β/γ Agonist Induces an ERRα-Depen…
- PMID 37961903 — 2024 · Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardia…
- PMID 41421047 — 2026 · An orally active estrogen receptor-related receptor agonist, SLU-PP-915,…
- PMID 37717940 — 2023 · Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and…
- PMID 41588687 — 2026 · In Vitro Metabolism and Analytical Characterization of SLU-PP-332 and SL…
- PMID 41688415 — 2026 · Analysis and Identification of In Vitro Metabolites of Exercise Mim…
- PMID 41850449 — 2026 · Chemical optimization of the exercise mimetic SLU-PP-332 enables insight…
- PMID 40692696 — 2025 · Targeting ERRs to counteract age-related muscle atrophy associated with …
- PMID 42024694 — 2026 · [Pharmacological Activation of ERRα/β/γ as an Exercise…
- PMID 42182218 — 2026 · ERRγ deletion in podocytes accelerates aging related kidney diseas…
- PMID 28780078 — 2017 · ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological P…