What it is
SLU-PP-332 is a synthetic small-molecule hydrazone (IUPAC name (E)-4-Hydroxy-N'-(naphthalen-2-ylmethylene)benzohydrazide; molecular formula C₁₈H₁₄N₂O₂; molecular weight 290.32 g/mol; CAS 303760-60-3; PubChem CID 5338394; alternate designation SR9861) that functions as a pan-agonist of the estrogen-related receptor subfamily ERRα, ERRβ, and ERRγ. The Z-configuration at the C=N hydrazone bond is required for ligand-binding-domain docking and pharmacological activity; the E/Z isomer ratio is a quality-control checkpoint for research-grade material. The compound was designed and first disclosed by the laboratory of Thomas Burris — then at the Scripps Research Institute in Florida, subsequently at Saint Louis University, and currently at the University of Florida — as part of a multi-year ERR medicinal-chemistry program. Unlike classical estrogen-receptor ligands, ERRs are orphan nuclear receptors that do not bind estrogen; they are constitutively active transcription factors whose principal role is to coordinate mitochondrial biogenesis, oxidative phosphorylation, and fatty-acid oxidation through the coactivator PGC-1α. SLU-PP-332 is not a peptide; Peptigrade covers it as a small-molecule investigational compound in the Metabolic & Weight category because it is being marketed into the same research-chemical channels as peptides such as AOD-9604 and retatrutide.
In plain English
SLU-PP-332 is a synthetic small molecule — NOT a peptide. It is included on this site because it is sold in the same research-chemical channels as metabolic peptides and performance compounds. Chemically it is called a hydrazone. It functions as a pan-agonist of the estrogen-related receptors (ERRα, ERRβ, ERRγ). Note: these are NOT the same as the estrogen receptors that control reproductive functions — ERRs are a separate family whose main job is to control mitochondrial energy production, fat burning, and muscle endurance. Turning ERRs on activates many of the same genes that aerobic exercise activates — which is why the compound is called an 'exercise mimetic.' The molecule has a strict geometric requirement: only the Z-form fits in the receptor's binding pocket and works. It was developed by the Thomas Burris laboratory (Saint Louis University, now University of Florida) and first published in 2023. It is not approved for human use anywhere in the world and has no published human safety or efficacy data.
How it works
- 01
ERRα/β/γ ligand binding and coactivator recruitment
Billon et al. 2023 (JBC, PMID 36988910) characterized SLU-PP-332 in cell-based cotransfection and reporter assays with EC₅₀ values of 98 nM at ERRα, 230 nM at ERRβ, and 430 nM at ERRγ, with selectivity over the classical estrogen receptors ERα and ERβ and a panel of unrelated nuclear receptors. Ligand docking to the ERR ligand-binding domain stabilizes the active conformation, strengthens the receptor's protein-protein interface with the coactivator PGC-1α, and increases transcriptional output at ERR-responsive elements (ERREs) on target genes. The Z-configuration at the hydrazone C=N bond is required for activity; the E-isomer is substantially less active in the same assays.
In plain English
It activates three related 'energy control switches' in cells
SLU-PP-332 binds to and activates three estrogen-related receptors — ERRα, ERRβ, ERRγ — which are proteins in the cell nucleus that control gene activity. It is most potent at ERRα (EC₅₀ 98 nM), with weaker activity at ERRβ and ERRγ. Critically, it does NOT activate the classical estrogen receptors that control reproductive tissues. When ERRs are activated, they recruit a co-activator protein (PGC-1α) that amplifies the signal and turns on energy-producing gene programs. Only the Z-form of the molecule fits in the receptor binding pocket — the other form (E) is largely inactive.
- 02
PGC-1α-driven mitochondrial biogenesis
Billon 2023 (Am J Pathol / PMC10801787) showed that SLU-PP-332 treatment in mice upregulates PGC-1α expression and downstream TFAM (mitochondrial transcription factor A), which drives mitochondrial DNA replication and the transcription of nuclear-encoded OXPHOS complex subunits. Skeletal-muscle mitochondrial density increased approximately 1.8-fold in treated mice. This is the same transcriptional axis activated by endurance exercise and by caloric restriction — the 'exercise-mimetic' framing derives from the overlap of the SLU-PP-332 gene-expression signature with the acute-aerobic-exercise program.
In plain English
It tells cells to build more mitochondria
When SLU-PP-332 activates ERRα, it boosts PGC-1α and then a downstream protein (TFAM) that drives cells to build more mitochondria — the cell's power generators. In treated mice, skeletal-muscle mitochondria increased roughly 1.8-fold. This is the same pathway activated by endurance exercise and caloric restriction. That overlap is the basis for calling SLU-PP-332 an 'exercise mimetic.'
- 03
Fatty-acid oxidation and metabolic substrate switch
Upregulation of β-oxidation enzymes (MCAD, LCAD, HADHA), carnitine-palmitoyltransferase 1 (CPT1), and mitochondrial OXPHOS machinery shifts skeletal-muscle substrate utilization toward fatty-acid oxidation and away from glycolysis in Billon's DIO-mouse cohort. The downstream phenotype — reduced adipocyte size, lower fat mass accumulation, normalized triglyceride and HDL profiles over 28 days at 50 mg/kg BID IP — is consistent with the transcriptional signature. AMPK activation has been described in the same preparations but is not the primary driver; the ERR→PGC-1α→OXPHOS axis is the proximate mechanism.
In plain English
It shifts muscles to burn fat instead of sugar
Downstream of mitochondrial biogenesis, SLU-PP-332 upregulates the enzymes that burn fat (β-oxidation enzymes) and the proteins that ferry fat into mitochondria. In obese mice, this shifted muscles to use fat as fuel instead of glucose. The results: smaller fat cells, lower total fat mass, better insulin sensitivity, and improved cholesterol and triglyceride levels over 28 days. This fat-burning shift is consistent with the mitochondrial gene program — but only tested in mice.
- 04
Type-IIa oxidative muscle-fiber remodeling and endurance phenotype
Billon 2023 (JBC) documented an ERRα-dependent increase in type-IIa (fast oxidative, fatigue-resistant) muscle fibers in quadriceps, with elevated cytochrome c, myosin-IIa, and mitochondrial DNA content. Treadmill running time increased by approximately 70% relative to vehicle. A muscle-specific ERRα-knockout line abolished the endurance effect, providing loss-of-function confirmation of target dependence. The phenotype is a transcriptional-program-induced fiber-type shift, not an acute contractile effect.
In plain English
It remodels muscle to be more like an endurance athlete's
In the JBC mouse study, SLU-PP-332 increased the proportion of type-IIa muscle fibers (fast oxidative, fatigue-resistant — the type highly trained endurance athletes have more of) in the quadriceps. Markers of mitochondrial density and oxidative capacity rose. Treadmill running time increased by roughly 70% vs vehicle. When researchers deleted the ERRα gene specifically in muscle cells, the endurance effect disappeared — confirming the mechanism. This is a gene-program-driven fiber-type change, not just a stimulant-like effect.
- 05
ERRγ-predominant cardiac and renal effects
Billon 2024 (Circulation meeting abstract) attributed the ejection-fraction improvement and reduced cardiac fibrosis observed after 6 weeks of treatment in the mouse TAC pressure-overload model predominantly to ERRγ, the isoform most highly expressed in cardiac tissue. Liu 2023 (JCI, PMID 37717940) in aged mice showed SLU-PP-332 restored mitochondrial function in renal podocytes and reduced cGAS-STING-driven inflammatory signaling — consistent with ERR-mediated upregulation of mitochondrial quality control. Both findings are single-lab rodent reports; neither has independent replication.
In plain English
It may also help heart and kidney energy systems through ERRγ
ERRγ — the third receptor in the family — is most highly expressed in the heart and kidneys. In mouse models: a 2024 Circulation abstract reported improved heart pumping and less scarring in a pressure-overload heart-failure model; a 2023 JCI paper reported reversal of age-related kidney damage and reduced inflammation in old mice. Both findings come from a single lab and have not been independently replicated.
- 06
What is NOT known about the mechanism
No human pharmacokinetic data have been published (oral bioavailability, plasma half-life, tissue distribution, metabolism, clearance route). No co-crystal structure of SLU-PP-332 bound to any ERR ligand-binding domain has been published in the peer-reviewed literature, so docking claims rest on homology modeling. The consequences of chronic ERR pan-agonism in humans — including potential effects on cardiac hypertrophy pathways, tumor mitochondrial metabolism (ERRα is upregulated in multiple cancers), and reproductive-tissue ERRβ signaling — are uncharacterized. The rodent exposure envelope in the published literature maxes out at 8 weeks.
In plain English
What we still don't understand
No human pharmacokinetic data exist — nobody knows how well SLU-PP-332 is absorbed from the gut, how long it stays in the blood, or how it is cleared. No co-crystal structure of the drug bound to an ERR receptor has been published — selectivity claims rest on cell tests and computer modeling. The consequences of long-term ERRα activation in people are unknown: ERRα is overexpressed in several cancers, and whether stimulating it long-term accelerates tumor metabolism is untested. ERRβ is essential in the placenta and reproductive tissues — reproductive toxicity is completely uncharacterized. The longest rodent exposure is 8 weeks.