SLU-PP-332

SLU-PP-332 is a synthetic small molecule developed at Saint Louis University School of Medicine. It functions as a potent, non-selective agonist of the estrogen-related receptors (ERRs), particularly ERRα, ERRβ, and ERRγ. By binding to these receptors, SLU-PP-332 enhances mitochondrial function and energy metabolism, mimicking some of the beneficial effects of exercise.

What Is SLU-PP-332

SLU-PP-332: Overview and Research Insights

SLU-PP-332 is a member of a class of compounds known as estrogen-related receptor agonists (ERR agonists). It has shown a range of effects in animal studies, including:

• Increased energy expenditure primarily by enhancing fat burning
• Improved exercise tolerance and physical endurance
• Enhanced mitochondrial density and function, leading to better muscle performance

What Are Estrogen-Related Receptors (ERRs)?

ERRs are orphan nuclear receptors, meaning their natural ligands remain unidentified. There are three main types:

• ERRα (alpha)
• ERRβ (beta)
• ERRγ (gamma)

Despite their name, ERRs are not regulated by estrogen; they were named due to genetic similarity with the estrogen receptor α gene.

ERRs regulate gene expression patterns impacting:

• Energy homeostasis
• Oxidative metabolism
• Mitochondrial biogenesis

Activating ERRs increases energy use and fatty acid oxidation, promoting fat loss. They also improve mitochondrial function in heart and skeletal muscles, enhancing cardiovascular health and endurance.

Importance of ERRs in Exercise Tolerance

Mouse models lacking ERR genes in skeletal muscle (knockout mice) show:

• Severe exercise intolerance
• Pale muscles with decreased oxidative capacity
• Inability to switch to lipid (fat) metabolism during exercise

ERRα controls genes related to glucose production, fatty acid metabolism, and brown fat thermogenesis, and regulates cholesterol, glucose, insulin, and triglyceride levels. It’s also a target of statin drugs.

ERRγ shares similar roles in mitochondrial activity and gene transcription. Notably, it is targeted by bisphenol A (BPA), an endocrine disruptor linked to metabolic syndrome and cancer, as BPA disrupts ERRγ’s regulation of mitochondrial function.

ERRγ is also under investigation for Parkinson’s disease, as its deficiency worsens synuclein toxicity, while overexpression can delay neurodegeneration. ERRγ agonists like SLU-PP-332 are being studied as potential treatments.

ERRβ mainly regulates pluripotent stem cell transitions, playing a role in tissue regeneration and development, but remains less understood.

Bioavailability and Significance of SLU-PP-332

SLU-PP-332 is notable for its ability to reach ERRs throughout the body in vivo (in living organisms), unlike many prior ERR agonists that were limited to in vitro use due to poor stability or bioavailability.

It is the first ERRα agonist developed, filling a major gap since ERRα was the first identified ERR. Its availability has significantly advanced exercise mimetic research.

SLU-PP-332 as an Exercise Mimetic

Exercise offers numerous health benefits, including improved weight control, muscle mass, bone strength, cardiovascular health, brain function, and slowed aging. However, barriers like lack of time or enjoyment motivate the search for "exercise in a pill."

Other exercise mimetics include:

• GLP-1 agonists (e.g., semaglutide) for appetite suppression and weight loss
• Growth hormone releasing hormone agonists (e.g., sermorelin, CJC-1295) to improve muscle and cardiovascular health
• Peptides like Selank and Semax that boost brain-derived neurotrophic factor for cognitive benefits

SLU-PP-332 uniquely enhances cellular respiration—the process by which mitochondria generate energy—resulting in:

• Increased basal metabolic rate
• Improved glucose tolerance and insulin sensitivity
• Greater stamina and endurance
• Growth of small blood vessels

In mice, SLU-PP-332 administered twice daily for a month led to a 12% body weight reduction without changes in exercise or food intake. It also alleviated metabolic syndrome.

SLU-PP-332 and Endurance

Increased ERRγ expression raises mitochondrial density in cells, enabling:

• Faster oxygen and nutrient use
• Delayed muscle fatigue
• Enhanced exercise capacity

ERRγ also boosts skeletal muscle blood vessel density, improving nutrient delivery and waste clearance. This increase correlates with better insulin sensitivity and lower diabetes risk.

Mice treated with SLU-PP-332 ran 70% longer and 45% farther than controls, due to enhanced energy generation supporting prolonged aerobic muscle activity and increased fat burning.

SLU-PP-332 and Muscle Function

ERR expression in muscle increases in response to exercise-induced stress. SLU-PP-332 mimics this effect by boosting ERR levels, improving oxygen and nutrient utilization, and thereby muscle function.

SLU-PP-332 and Heart Health

SLU-PP-332 is a pan-ERR agonist, activating all ERR types. In mouse models of heart failure, it:

• Improves ejection fraction (heart pumping efficiency)
• Reduces cardiac fibrosis (scar tissue)
• Increases survival rates
• Normalizes heart fatty acid oxidation and energy balance

By regulating autophagy via transcription factor EB (TFEB), ERR activation helps remove damaged cells and scar tissue, preserving heart function and preventing arrhythmias.

SLU-PP-332 and Brain Health

Parkinson’s disease involves dopaminergic neuron loss and accumulation of alpha-synuclein forming Lewy bodies. These neurons are especially vulnerable to oxidative stress and mitochondrial dysfunction.

Research shows:

• Reduced mitochondrial gene expression in Parkinson’s patients
• ERRγ maintains mitochondrial content and regulates genes for autophagy, metabolism, and neuron function

Thus, ERRγ agonists like SLU-PP-332 offer hope for future Parkinson’s treatments.

SLU-PP-332, Caloric Restriction, and Aging

Kidney function declines with age, often worsened by hypertension and metabolic syndrome causing inflammation and mitochondrial dysfunction.

Studies show:

• ERR levels decrease with age in kidneys, except in individuals practicing lifelong calorie restriction
• Calorie restriction improves kidney function and reduces inflammation and mitochondrial dysfunction
• SLU-PP-332 administration mimics calorie restriction benefits, particularly via ERRα activation

Mitochondrial dysfunction contributes to aging through increased free radical production, which damages cells and promotes senescence or cancer. SLU-PP-332 is the first compound shown to directly improve mitochondrial health, a major anti-aging target.

Other ERR Agonists

Besides SLU-PP-332, two other major ERR agonists under study are:

• SLU-PP-1072: Primarily targets ERRα and ERRγ; studied for mitochondrial function in muscle and apoptosis induction in prostate cancer cells.
• SLU-PP-915: Structurally distinct; mainly investigated for heart failure benefits similar to SLU-PP-332, including improved cardiac function and reduced fibrosis.

Summary

SLU-PP-332 is an estrogen-related receptor agonist with strong affinity for ERRα and ERRγ. It enhances mitochondrial energy production, reduces oxidative stress, and improves endurance and exercise tolerance. It shows promise in heart and kidney protection, and potential neuroprotection in Parkinson’s disease. SLU-PP-332 represents a breakthrough in exercise mimetic research and mitochondrial health, opening avenues for novel therapeutic compounds.

Research Applications

SLU-PP-332 is primarily utilized in scientific studies focusing on:

• Metabolic Health: Investigating its potential to improve insulin sensitivity, reduce adiposity, and enhance glucose metabolism.
• Exercise Mimetics: Studying its ability to replicate certain physiological effects of exercise, such as increased mitochondrial biogenesis and enhanced muscle endurance.
• Cardiovascular Function: Exploring its impact on heart health, including potential protective effects against heart failure and ischemic injury.
• Aging and Longevity: Assessing its role in mitigating age-related mitochondrial dysfunction and promoting cellular health.

Product Specifications

• Form: Capsules containing lyophilized (freeze-dried) SLU-PP-332 powder.
• Dosage: Each capsule contains 250mcg of SLU-PP-332.
• Quantity: Typically available in bottles containing 60 capsules.
• Purity: ≥99%, ensuring high-quality material for research purposes.
• Packaging: Sealed bottles to maintain product integrity.
• Storage: Store in a cool, dry place away from direct sunlight.

Safety and Handling

SLU-PP-332 is intended strictly for laboratory research and is not approved for human consumption. Handle with care, following appropriate safety protocols. Ensure proper storage conditions to maintain the integrity and efficacy of the compound.

Resources

• Nasri, H. (2024). New hopes on SLU-PP-332 for weight loss and kidney protection. J Ren Endocrinol, 10(1). 
• Wattez, J.-S. et al. (2023). Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance. Mol Metab, 68, 101670. 
• Xin, F. et al. (2018). Endocrine-disrupting chemicals, epigenetics, and skeletal system dysfunction: Bisphenol A as a model. Environ Epigenet, 4(2), dvy002. 
• Fox, S.N. et al. (2022). Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy. npj Parkinsons Dis, 8(1), 1–19. 
• Billon, C. et al. (2023). Synthetic ERRα/γ agonist induces aerobic exercise response and enhances exercise capacity. ACS Chem Biol, 18(4), 756–771. 
• Hawley, J.A., Joyner, M.J., Green, D.J. (2021). Mimicking exercise: what matters most and where to next? J Physiol, 599(3), 791–802. 
• Badin, P.-M. et al. (2016). Exercise-like effects by estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice. Sci Rep, 6, 26442. 
• Xu, W. et al. (2024). Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function. Circulation, 149(3), 227–250. 
• Losby, M. et al. (2024). The estrogen receptor-related orphan receptors regulate autophagy through TFEB. Mol Pharmacol, 106(4), 164–172. 
• Wang, X.X. et al. (2023). Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney. Am J Pathol, 193(12), 1969–1987. 
• Miwa, S. et al. (2022). Mitochondrial dysfunction in cell senescence and aging. J Clin Invest, 132(13), e158447. 
• Schoepke, E. et al. (2020). Selective ERRα inverse agonist inhibits Warburg effect and induces apoptosis in prostate cancer cells. ACS Chem Biol, 15(9), 2338–2345. 
• Rodriguez, A. (2025). Novel approach improves heart failure outcomes in animal model. Baylor College of Medicine Blog.