Identity and class
SLU-PP-332 is a synthetic small-molecule agonist of the estrogen-related receptors (ERRα, ERRβ, and ERRγ), that is, a "pan-ERR" agonist, developed in the laboratory of Thomas Burris (Saint Louis University School of Medicine; hence the "SLU" prefix). It is not a peptide: chemically it is an acylhydrazone (an aryl hydrazone, a Schiff base), (E)-4-hydroxy-N'-(naphthalen-2-ylmethylene)benzohydrazide, molecular formula C₁₈H₁₄N₂O₂, molar mass ≈290.3 g/mol, CAS (Chemical Abstracts Service registry number) 303760-60-3. In popular science writing it is called an "exercise mimetic," because in rodents it reproduces part of the transcriptional and metabolic response that acute aerobic exercise normally triggers.
The compound is not a primary "from scratch" discovery but a product of optimizing a previously known, weaker ERR tool compound, GSK4716: replacing its isopropylphenyl fragment with a naphthalene ring increased affinity for ERRα and extended activity across all three isoforms (see the "Chemistry, analytics, and analogs" section). This material is strictly for research reference use (RUO): it is a laboratory research reagent, not an agent for human or animal use.
Target: the estrogen-related receptors (ERR)
The ERRs (nomenclature NR3B1–3: ERRα, ERRβ, ERRγ) are orphan nuclear receptors that, despite their name and structural kinship with the classical estrogen receptors (ERα/ERβ), do not bind estrogen and have no proven endogenous ligand, although cholesterol and some of its derivatives have been discussed as possible natural ligands of ERRα, the question remains unresolved. ERRs are constitutively active transcription factors: they are continuously bound to DNA, and agonists tend to reinforce an already-existing program rather than "switch it on" from scratch.
The isoforms differ in tissue expression: ERRα is the most broadly expressed, peaking in heart, muscle, kidney, brown adipose tissue, and liver; ERRγ is enriched in heart, slow-twitch muscle fibers, and brain; ERRβ has a narrower profile (placenta, inner ear, embryonic development) and is the least studied in adult metabolism. In complex with PGC-1 coactivators (primarily PGC-1α), ERRs bind ERRE elements in promoters and govern genes of mitochondrial biogenesis, the electron transport chain, fatty acid oxidation, and the Krebs cycle, which is why ERR agonism is studied as a way to reproduce part of exercise's effects on tissue oxidative capacity [4].
Molecular mechanism
SLU-PP-332 binds in the ligand-binding domain (LBD) of ERR and stabilizes helix 12 (the AF-2 domain) in the active conformation, enhancing coactivator recruitment via their LXXLL motifs, primarily PGC-1 and SRC. The compound is most potent at ERRα (EC₅₀ ~100 nM, ~98 nM by some summaries), with somewhat weaker activity at ERRβ (~230 nM) and ERRγ (~430 nM), unlike GSK4716 (practically inactive at ERRα) and DY131 (predominantly ERRβ/γ, weak at ERRα).
| Compound | ERRα (EC₅₀) | ERRβ (EC₅₀) | ERRγ (EC₅₀) | Profile |
|---|---|---|---|---|
| SLU-PP-332 | ~98 nM | ~230 nM | ~430 nM | balanced pan-ERR agonist |
| GSK4716 (precursor) | practically inactive | ~215–340 nM | ~215–340 nM | ERRβ/γ-selective |
| DY131 | weak activity | moderate | predominant | ERRβ/γ with a skew toward ERRγ |
| SLU-PP-915 (successor) | ~400 nM | ~400 nM | ~400 nM | pan-ERR, orally bioavailable |
Downstream, the compound reinforces the ERR/PGC-1α program: it upregulates genes for fatty acid oxidation, the electron transport chain, and mitochondrial biogenesis, which in muscle reproduces the signature of an endurance training session. It does not act through the classical estrogen-receptor pathway and has no affinity for ERα/ERβ, distinguishing it from phytoestrogens and estrogen receptor modulators.
Preclinical data: exercise mimicry and endurance
In the foundational study from the Burris laboratory (ACS Chemical Biology, 2023), administering SLU-PP-332 to sedentary mice induced an ERRα-dependent "acute aerobic exercise" gene program in skeletal muscle, a signature featuring transient upregulation of Ddit4 (a regulator that physiologically appears after exercise) and Slc25a25 (a mitochondrial ATP-Mg²⁺/Pi carrier) [1], which reproduced a substantial portion of the signature seen with actual treadmill running.
Chronic administration increased the proportion of oxidative type IIa fibers and increased running endurance (time and distance), and the effect disappeared completely in ERRα-knockout mice, establishing ERRα as the mechanistically required receptor [1]. The effect was observed both after a single acute dose and after repeated dosing. Exposure was moderate (~0.2 µM in plasma, ~0.6 µM in muscle 6 hours after an intraperitoneal dose), and administration was exclusively by injection, unlike the oral bioavailability of the later analog SLU-PP-915 (see the "Chemistry, analytics, and analogs" section).
Preclinical data: energy expenditure and obesity
In a related study from the same group (JPET, 2024), SLU-PP-332 was tested at a dose of 50 mg/kg twice daily, intraperitoneally, in mice with diet-induced and genetic obesity [2]. Treatment increased resting energy expenditure, increased fatty acid oxidation (by approximately 25% versus vehicle), reduced fat-mass gain without changing food intake (meaning the effect was not explained by appetite suppression) and improved glucose tolerance, with lower fasting glucose and insulin levels [2].
The authors interpret this as proof of concept: pharmacological activation of ERR can reproduce part of exercise's metabolically favorable effects without the exercise itself, and they propose ERR agonism as a strategy against metabolic syndrome. The conclusion is drawn exclusively from mouse models; there is no data on effects on body weight, glycemia, or energy expenditure in humans.
Other research directions
ERR agonism via SLU-PP-332 has also been studied outside the purely metabolic and muscular context. In a kidney aging model (The American Journal of Pathology, 2023), 21-month-old C57BL/6 mice (versus 4-month-old young controls) were given SLU-PP-332 at 25 mg/kg per day, intraperitoneally, for eight weeks [3]. Treatment reversed age-related changes across several measures at once: it reduced albuminuria and podocyte loss (as measured by NPHS2), restored the mitochondrial-to-nuclear DNA ratio and the respiratory capacity of isolated mitochondria, and lowered pro-inflammatory cytokines (IL-1β, TNF-α), cGAS-STING activation, and the senescence marker p21/Cdkn1a; electron microscopy confirmed restoration of mitochondrial morphology [3].
In a pressure-overload heart failure model (transverse aortic constriction, TAC, Circulation, 2024), SLU-PP-332 and the later SLU-PP-915 improved ejection fraction, reduced myocardial fibrosis, and increased survival, without affecting the hypertrophy itself, meaning they acted through the metabolic component of remodeling, via enhanced fatty acid oxidation and mitochondrial function in cardiomyocytes [6].
A separate, newer direction is the role of ERR agonism in age-related muscle atrophy associated with physical inactivity. A 2025 pilot study (Frontiers in Physiology) used primary human myoblasts from muscle biopsies of elderly women (mean age ~78 years), divided into active and sedentary groups (10 subjects each) [9]. Treating myoblasts from the sedentary group with SLU-PP-332 (10 µM, 48 hours) reduced cytotoxicity, oxidative stress (ROS), and cellular senescence (SA-β-galactosidase), and raised glutathione and levels of SIRT1, PGC-1α, ERRα, FNDC5, Akt, and Bcl-2 to values matching the active group; after 15 days of differentiation, the cells formed proper myotubes instead of the impaired myotube formation seen in the untreated control [9]. This is the first report of an SLU-PP-332 effect in human cells, though it is still a pilot, ex vivo study.
Chemistry, analytics, and analogs
The acylhydrazone scaffold is straightforward to synthesize, via condensation of 2-naphthaldehyde with 4-hydroxybenzohydrazide, yielding SLU-PP-332 as a white crystalline product; identity and purity are confirmed by HPLC (high-performance liquid chromatography) and mass spectrometry. As noted above, the compound itself is the result of optimizing the earlier tool compound GSK4716 by replacing its isopropylphenyl fragment with a naphthalene ring.
Because the parent molecule has limited drug-like properties (moderate exposure, injectable administration only), medicinal chemistry work has proceeded along two paths. The first is the successor SLU-PP-915: replacing the phenolic hydrogen-bond donor with a phenylboronic acid preserved activity across all ERR isoforms (EC₅₀ ~400 nM) and improved metabolic stability and oral bioavailability; it is SLU-PP-915, not SLU-PP-332, that is now being studied as an oral candidate in analogous models [6]. The second is a 2026 structure-activity relationship (SAR) study (IJBM) that systematically varied substituents on the scaffold, combining synthesis, cell-based assays, and binding modeling, and described analogs with improved ligand efficiency and stability [5].
A separate branch of SLU-PP-332 analytical chemistry is anti-doping analytics: given the nature of its action (an "exercise mimetic"), the compound has come to the attention of anti-doping laboratories. A 2026 study (Rapid Communications in Mass Spectrometry), using liquid chromatography (LC) coupled with high-resolution mass spectrometry (MS), i.e. LC-HRMS/MS, incubated SLU-PP-332 and SLU-PP-915 with S9 fraction and human liver microsomes and identified nine SLU-PP-332 metabolites (six phase I, three phase II) [7]. An independent study from the same year (Drug Testing and Analysis, UCLA laboratory), under different conditions, found a broader set (22 metabolites) for anti-doping detection markers [8]; the discrepancy is explained by incubation conditions, not by conflicting data.
Maturity of the evidence base
All data on the efficacy and mechanism of SLU-PP-332 come from cell-based assays, rodent experiments, and (in at least one pilot study) primary human cells ex vivo. There are no clinical trials, no human pharmacokinetic or safety data, and no regulatory approvals. Below is a summary of the models and key findings of the main preclinical sources.
| Study | Model | Key finding |
|---|---|---|
| Billon 2023 [1] | sedentary mice, 50 mg/kg i.p. | ERRα-dependent exercise gene program, increased endurance and proportion of type IIa fibers |
| Billon 2024 [2] | obese mice, 50 mg/kg×2 i.p. | higher energy expenditure and fat oxidation, improved glucose tolerance |
| Wang 2023 [3] | old (21-mo.) mice, 25 mg/kg/day, 8 wk | reversal of mitochondrial dysfunction, inflammation, and albuminuria in the kidney |
| Xu 2024 [6] | TAC heart-failure mice | higher ejection fraction, less fibrosis, higher survival |
| Bonanni 2025 [9] | human myoblasts, ex vivo, 10 µM | less oxidative stress and cellular senescence, restored myotube formation |
| Okda 2026 [5] | cell-based assays + modeling | structural determinants of potency and selectivity |
| Möller / Avliyakulov 2026 [7,8] | human liver S9/microsomes | metabolite mapping for anti-doping detection |
Each finding comes from a separate model, not from a picture replicated by multiple independent groups. The literature is growing (at least three new papers during 2026), but it remains small and concentrated around the discovering laboratory; these are preclinical, hypothesis-generating signals, not proven effects in humans.
Dosing and use status (RUO)
No confirmed human dose exists. The regimens reported in the literature for rodents (50 mg/kg twice daily, intraperitoneally, for endurance and metabolic syndrome; 25 mg/kg/day for eight weeks for the kidney aging model) are experimental protocols tied to a specific model and study duration; they cannot be extrapolated to humans. A simple allometric mg/kg conversion accounts for neither interspecies differences in pharmacokinetics nor the fact that SLU-PP-332 itself (unlike the oral SLU-PP-915) has no confirmed oral bioavailability at all.
SLU-PP-332 is supplied strictly as a research reagent for in-vitro and preclinical laboratory research. It is not a drug, not a dietary supplement, and not a food product; it is not intended for human or animal consumption, and nothing stated here is medical advice or a dosing recommendation.
References
- Billon C, Sitaula S, Banerjee S, Welch R, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. ACS Chemical Biology (2023). doi:10.1021/acschembio.2c00720
- Billon C, Schoepke E, Avdagic A, Chatterjee A, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. The Journal of Pharmacology and Experimental Therapeutics (2024). doi:10.1124/jpet.123.001733
- Wang XX, Myakala K, Libby AE, Krawczyk E, et al. Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney. The American Journal of Pathology (2023). doi:10.1016/j.ajpath.2023.07.008
- Audet-Walsh É, Giguère V. The multiple universes of estrogen-related receptor α and γ in metabolic control and related diseases. Acta Pharmacologica Sinica (2015). doi:10.1038/aps.2014.121
- Okda HE, Zhao P, Hayes M, Duvall C, et al. Chemical optimization of the exercise mimetic SLU-PP-332 enables insight into estrogen-related receptor signaling. International Journal of Biological Macromolecules (2026). doi:10.1016/j.ijbiomac.2026.151450
- Xu W, Billon C, Li H, Wilderman A, et al. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function. Circulation (2024). doi:10.1161/CIRCULATIONAHA.123.066542
- Möller T, Krug O, Thevis M. In Vitro Metabolism and Analytical Characterization of SLU-PP-332 and SLU-PP-915: Novel Pan-ERR Agonists With Doping Potential. Rapid Communications in Mass Spectrometry (2026). doi:10.1002/rcm.70039
- Avliyakulov NK, Sobolevsky T, Ahrens E. Analysis and Identification of In Vitro Metabolites of Exercise Mimetic SLU-PP-332 ERRα/β/γ Agonist for Doping-Control Purposes. Drug Testing and Analysis (2026). doi:10.1002/dta.70035
- Bonanni R, Falvino A, Matticari A, Rinaldi AM, et al. Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study. Frontiers in Physiology (2025). doi:10.3389/fphys.2025.1616693