Your cells think you just ran a marathon - you didn't. SLU-PP-332 did.

What if a single molecule could convince your cells they had just completed an intense endurance workout — without you moving a single muscle? That is precisely the ambition behind SLU-PP-332, a first-in-class synthetic pan-agonist of the Estrogen-Related Receptors (ERRα, ERRβ, and ERRγ). Originally developed at Saint Louis University and characterized in a landmark 2023 study by Billon et al. in ACS Chemical Biology, SLU-PP-332 activates a transcriptional program that mirrors the molecular signature of sustained aerobic exercise.

Mechanism: Turning on the Power Plant

Think of your cells as factories. Every factory runs on electricity — in biological terms, that electricity is ATP (adenosine triphosphate), produced inside mitochondria. As we age, these power plants shrink in number, become less efficient, and accumulate damage. SLU-PP-332 acts like a master electrician who upgrades the entire grid.

At the molecular level, SLU-PP-332 binds to all three ERR nuclear receptors, which function as transcription factors — essentially switches that turn genes on or off. When activated, ERRs drive upregulation of:

• PGC-1α — the master regulator of mitochondrial biogenesis. More mitochondria means more capacity to produce ATP.
• CPT1 (Carnitine Palmitoyltransferase 1) — the gateway enzyme that ferries fatty acids into the mitochondria for oxidation. Upregulating CPT1 shifts the cell from burning sugar to burning fat, the metabolically cleaner fuel.
• TFAM (Mitochondrial Transcription Factor A) — drives replication of mitochondrial DNA, literally building new power plants from scratch.
• COX5A (Cytochrome c Oxidase Subunit 5A) — a key component of the electron transport chain, enhancing the efficiency of ATP synthesis.
• PDK4 — suppresses glucose oxidation, ensuring that fatty acids, not carbohydrates, serve as the primary fuel substrate during fasting or energy-demanding states.

The Metabolic Shift: From Sugar Burner to Fat Burner

The respiratory exchange ratio (RER) — a clinical measure of which fuel substrate the body is burning — provides a measurable readout of SLU-PP-332's effects. A ratio of 1.0 reflects pure carbohydrate oxidation; 0.70 reflects near-complete fatty acid oxidation. Mechanistic data predict that SLU-PP-332 treatment would push the RER toward 0.70–0.80, particularly under fasting or exercise conditions. This metabolic shift is not merely cosmetic — it reflects a fundamental rewiring of cellular energy preference toward oxidative, mitochondria-dependent metabolism.

Exercise Without Exercise

In the 2023 ACS Chemical Biology study (PMID: 36988910), SLU-PP-332 was shown to activate ERRα-dependent transcription of genes associated with aerobic exercise — including those involved in fatty acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis — in skeletal muscle cells and in vivo in mice. Treated animals demonstrated enhanced exercise capacity and improved running endurance, with transcriptomic profiles closely resembling those of endurance-trained subjects.

The compound selectively activates ERRα with the highest potency (EC50 in the low nanomolar range), while also engaging ERRβ and ERRγ — creating a broad-spectrum metabolic activation that coordinates energy metabolism across multiple tissue types simultaneously.

Clinical Implications

The implications extend far beyond sports performance. Conditions defined by mitochondrial dysfunction — including metabolic syndrome, heart failure, chronic kidney disease, neurodegeneration, and age-related muscle loss — all share a common pathological thread: failing energy metabolism. SLU-PP-332 targets this thread at its source. It does not simply treat symptoms; it addresses the underlying biological machinery that drives cellular decline.

Warning:
SLU-PP-332 is a research compound not approved for human use. This content is produced exclusively for educational and informational purposes. Nothing contained herein constitutes or should be interpreted as medical advice, a clinical recommendation, a diagnostic opinion, or an endorsement of any specific treatment, supplement, or intervention. Always consult a qualified and licensed medical professional before making decisions regarding your health, supplementation, or medical care. The author and publisher of this content accept no liability for any actions taken or not taken based on the information provided herein.

Bibliography & Sources

Billon C, Sitaula S, Banerjee S, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. ACS Chemical Biology. 2023;18(4):756–771. doi:10.1021/acschembio.2c00720. PMID: 36988910. 

Billon C, Schoepke E, Avdagic A, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. Journal of Pharmacological and Experimental Therapeutics. 2024;388(2):232–240. doi:10.1124/jpet.123.001733. PMID: 37739806. 

Okda HE, Zhao P, Hayes M, et al. Chemical Optimization of the Exercise Mimetic SLU-PP-332 Enables Insight into Estrogen-Related Receptor Signaling. International Journal of Biological Macromolecules. 2026;355:151450. doi:10.1016/j.ijbiomac.2026.151450. PMID: 41850449. 

de Souza-Lima J, Astrosa-Martin BD, et al. Pharmacological Activation of ERRα/β/γ as an Exercise Mimetic: Potential Therapeutic Applications. Revista Médica de Chile. 2026;154(2):237–245. doi:10.4067/s0034-98872026000200237. PMID: 42024694. 

Billon C, Appourchaux K, Côté I, Burris TP. An Orally Active Estrogen Receptor-Related Receptor Agonist, SLU-PP-915, Enhances Aerobic Exercise Capacity. Journal of Pharmacological and Experimental Therapeutics. 2026;393(1):103787. doi:10.1016/j.jpet.2025.103787. PMID: 41421047.