Abstract
Cardarine (GW-501516), a potent PPARδ (PPARβ/δ) agonist, and SLU-PP-332, a pan-ERR (estrogen-related receptor) agonist with high potency at ERRα, each activate complementary metabolic programs that increase fatty-acid oxidation, mitochondrial function, and endurance-like phenotypes in animal models. Preclinical evidence suggests the two drug classes could be mechanistically complementary: PPARδ activation shifts substrate use toward lipids and increases oxidative gene expression, while ERR agonism promotes mitochondrial biogenesis and respiration. Together, they may produce additive or synergistic improvements in energy expenditure, fatty-acid oxidation and endurance-type phenotypes in preclinical models. However, Cardarine’s documented carcinogenic signal in long-term rodent studies and the limited human safety data for both agents mandate extreme caution; any combined use outside tightly controlled, approved research would be speculative and potentially hazardous. This paper summarizes chemistry (CAS numbers), mechanisms, preclinical evidence, putative synergy, safety concerns, research recommendations, SEO keywords, and a 10-item FAQ. DrugBank+2PMC+2
Chemical identity & identifiers
- Cardarine (also: GW-501516, GW1516, Endurobol)
- Class / target: PPARδ (PPARβ/δ) agonist.
- CAS number: 317318-70-0. DrugBank
- SLU-PP-332 (slupp332)
- Class / target: Estrogen-related receptor (ERR) pan-agonist (highest potency at ERRα).
- CAS number (commonly listed): 303760-60-3. Enzo+1
(When referencing supplier catalogues or PubChem/DrugBank entries, verify the CAS on the vendor Certificate of Analysis for the exact product form you intend to study.) DrugBank+1
Mechanisms of action — how each compound works (concise)
Cardarine (PPARδ agonism)
- Activates PPARδ transcriptional programs that upregulate genes for fatty-acid transport and β-oxidation in skeletal muscle and liver, shifting fuel preference toward lipids and increasing endurance-type adaptations in rodents. PMC+1
SLU-PP-332 (ERR agonism)
- Activates estrogen-related receptors (ERRα/β/γ), nuclear receptors that regulate mitochondrial biogenesis, oxidative phosphorylation, and genes involved in cellular respiration — producing an “exercise-mimetic” transcriptional program in skeletal muscle and other tissues. SLU-PP-332 has been shown in mice to increase fatty-acid oxidation, energy expenditure, endurance phenotypes, and to upregulate mitochondrial genes. PMC+1
Convergence points
- Both classes converge on improved mitochondrial fatty-acid utilization and oxidative capacity, but do so via different transcriptional regulators: PPARδ controls lipid-metabolic enzymes and fuel-selection programs while ERRs more directly promote mitochondrial biogenesis and respiratory chain components. This complementary biology forms the theoretical basis for synergy. PMC+1
Preclinical evidence (selected, load-bearing references)
- Cardarine (GW-501516): a strong preclinical literature shows increased fatty-acid oxidation, endurance, and favorable metabolic markers after PPARδ activation. However, GSK-sponsored long-term rodent carcinogenicity studies revealed accelerated tumor formation in multiple organs with chronic GW-501516 exposure, leading to termination of clinical development. These safety signals are a major constraint on translational use. PMC+1
- SLU-PP-332: multiple recent studies show SLU-PP-332 increases mitochondrial respiration, boosts whole-body energy expenditure, reduces adiposity and improves insulin sensitivity in mouse models and enhances endurance-like metrics; it has been characterized as an ERR pan-agonist and exercise-mimetic in rodents. PMC+1
- Combined / comparative data: there are few (if any) peer-reviewed studies directly testing Cardarine + SLU-PP-332 together. Theoretical synergy is supported by independent studies showing complementary modulation of fatty-acid oxidation (PPARδ) and mitochondrial biogenesis/respiration (ERR agonists), but empirical combination studies are needed. PMC+1
Why they might work synergistically — biological rationale
- Complementary transcriptional control: PPARδ increases expression of lipid-handling enzymes and transporters (improving substrate availability and β-oxidation), while ERR agonism increases the mitochondrial machinery needed to oxidize those substrates — together improving throughput (supply + capacity). PMC+1
- Enhanced mitochondrial capacity + substrate shift: ERR-driven mitochondrial biogenesis could magnify the downstream effect of PPARδ-driven lipid mobilization, leading to greater fatty-acid oxidation and energy expenditure than either agent alone. PMC+1
- Distinct but overlapping tissue profiles: PPARδ effects are strong in skeletal muscle and liver; ERRs (particularly ERRα) are central controllers of mitochondrial gene programs in muscle and heart — combining might broaden tissue coverage for metabolic remodeling. PMC+1
Important caveat: mechanistic complementarity does not equal safety. Interactions at the level of transcriptional networks, ROS production, angiogenesis, or cell-proliferation pathways could produce unexpected risks (see Safety section). Empirical co-administration studies — with appropriate toxicology, genotoxicity and long-term carcinogenicity endpoints — are essential before any translational claims. PMC+1
Research Suggests
Preclinical evidence (selected, load-bearing references)
- Cardarine (GW-501516): a strong preclinical literature shows increased fatty-acid oxidation, endurance, and favorable metabolic markers after PPARδ activation. However, GSK-sponsored long-term rodent carcinogenicity studies revealed accelerated tumor formation in multiple organs with chronic GW-501516 exposure, leading to termination of clinical development. These safety signals are a major constraint on translational use. PMC+1
- SLU-PP-332: multiple recent studies show SLU-PP-332 increases mitochondrial respiration, boosts whole-body energy expenditure, reduces adiposity and improves insulin sensitivity in mouse models and enhances endurance-like metrics; it has been characterized as an ERR pan-agonist and exercise-mimetic in rodents. PMC+1
- Combined / comparative data: there are few (if any) peer-reviewed studies directly testing Cardarine + SLU-PP-332 together. Theoretical synergy is supported by independent studies showing complementary modulation of fatty-acid oxidation (PPARδ) and mitochondrial biogenesis/respiration (ERR agonists), but empirical combination studies are needed. PMC+1
Why they might work synergistically — biological rationale
- Complementary transcriptional control: PPARδ increases expression of lipid-handling enzymes and transporters (improving substrate availability and β-oxidation), while ERR agonism increases the mitochondrial machinery needed to oxidize those substrates — together improving throughput (supply + capacity). PMC+1
- Enhanced mitochondrial capacity + substrate shift: ERR-driven mitochondrial biogenesis could magnify the downstream effect of PPARδ-driven lipid mobilization, leading to greater fatty-acid oxidation and energy expenditure than either agent alone. PMC+1
- Distinct but overlapping tissue profiles: PPARδ effects are strong in skeletal muscle and liver; ERRs (particularly ERRα) are central controllers of mitochondrial gene programs in muscle and heart — combining might broaden tissue coverage for metabolic remodeling. PMC+1
Important caveat: mechanistic complementarity does not equal safety. Interactions at the level of transcriptional networks, ROS production, angiogenesis, or cell-proliferation pathways could produce unexpected risks (see Safety section). Empirical co-administration studies — with appropriate toxicology, genotoxicity and long-term carcinogenicity endpoints — are essential before any translational claims. PMC
Potential benefits (preclinical / hypothetical)
- Increased whole-body fatty-acid oxidation and energy expenditure. PMC+1
- Enhanced endurance-like phenotypes (improved exercise capacity in rodents). PMC+1
- Improved metabolic parameters (insulin sensitivity, reduced adiposity) in diet-induced obese models. PMC+1
- Potential additive gains in mitochondrial density/function plus substrate availability — theoretically enhancing performance or metabolic health in preclinical systems. PMC+1
Research recommendations (preclinical)
- In vitro co-transcriptional profiling: treat relevant cell types (human primary myotubes, hepatocytes, cardio myocytes) with each compound and the combination, then perform RNA-seq to map convergent/divergent programs. PMC+1
- Short-term safety & functional studies in rodents: measure endurance, metabolic rate, mitochondrial markers, plus early toxicity markers (liver/kidney panel, proliferation markers).
- Long-term carcinogenicity and genotoxicity: mandatory for translational progression, especially given Cardarine’s history.
- Dose-range finding & PK/PD cross-interaction studies: to identify exposure–response and any pharmacokinetic interactions.
- Mechanistic assays for ROS, angiogenesis and proliferation: test the combination’s effects on angiogenic factors and cell-cycle regulators.
(These are research-design suggestions, not clinical instructions.) PMC+1
SEO keywords & metadata (to help the page rank for research/educational queries)
Primary keywords: Cardarine GW-501516, SLU-PP-332, slupp332, PPARδ agonist, ERR agonist, exercise mimetic, mitochondrial biogenesis, fatty-acid oxidation, metabolic syndrome research.
Secondary / long-tail keywords: Cardarine and SLU-PP-332 synergy, GW501516 CAS 317318-70-0, SLU-PP-332 CAS 303760-60-3, combine PPARδ and ERR agonists, exercise mimetic research paper, research chemicals PPARδ ERR, preclinical metabolic enhancers.
SEO meta description (suggested): “Research review of Cardarine (GW-501516, CAS 317318-70-0) combined with SLU-PP-332 (CAS 303760-60-3): mechanisms, theoretical synergy for mitochondrial function and fatty-acid oxidation, and critical safety considerations including carcinogenicity signals for Cardarine. For research use only.”
Tips to rank: include PubMed/PMC links for claims, add structured data (Article schema), use H1/H2 headings, add a small table summarizing citations (author, year, model, outcome), and keep page load fast with optimized images/infographics summarizing mechanisms. DrugBank+1
Representative citations (open access where possible)
- Billon C, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. J Pharmacol Exp Ther / PMC. 2024. (SLU-PP-332 exercise-mimetic evidence). PMC
- Smith RW, et al. Therapeutic potential of GW501516 and the role of PPARδ. Review, PMC. 2016. (PPARδ biology and metabolic effects). PMC
- Pollock CB, et al. Induction of metastatic gastric cancer by peroxisome proliferator-activated receptor δ activation. PMC. 2010. (Examples of PPARδ agonist promotion of tumorigenesis in certain models). PMC
- USADA / anti-doping and regulatory advisory material on GW1516/Cardarine (safety and prohibited status). NPC Hello
10 Frequently Asked Questions (FAQ)
1. What are Cardarine and SLU-PP-332?
Cardarine (GW-501516) is a PPARδ agonist that promotes fatty-acid oxidation and endurance phenotypes in animals. SLU-PP-332 is a pan-ERR agonist (strongest at ERRα) that promotes mitochondrial biogenesis and respiration. Both are research compounds studied in preclinical models. PMC+1
2. What are the CAS numbers?
Cardarine (GW-501516): 317318-70-0. SLU-PP-332: 303760-60-3. Verify vendor CoAs for exact product forms. DrugBank+1
3. Why would someone consider combining them?
Mechanistically they target complementary nodes of energy metabolism — PPARδ shifts substrate use toward fats and upregulates fatty-acid oxidation genes, while ERR agonists increase mitochondria and respiratory capacity. Together they could theoretically amplify oxidative metabolism in preclinical systems. However, this is theoretical and requires careful testing. PMC+1
4. Are there published studies of the combination?
As of the cited literature, direct, peer-reviewed combination studies are sparse or absent. The hypothesis of synergy is based on independent studies of each agent. Dedicated combination studies (including safety endpoints) are needed. PMC+1
5. What are the main safety concerns?
Cardarine has documented carcinogenicity in long-term rodent studies, which ended its clinical development; this is a major safety flag. SLU-PP-332 lacks robust human safety data. Combining two powerful nuclear-receptor agonists could magnify unknown risks, including tumor promotion, oxidative stress, or organ toxicity. PMC+1
6. Are these compounds approved for human use?
No. Cardarine is not approved for therapeutic use (development halted). SLU-PP-332 is a research compound under preclinical study. Both are typically sold for laboratory research only. DrugBank+1
7. Could combined use improve athletic performance?
Preclinical models show endurance-like benefits from each class. Theoretical synergy could affect endurance/metabolism, but athlete use is unsafe and prohibited by anti-doping agencies. Human effects and long-term safety have not been established. PMC+1
8. What experiments should researchers run first?
Start with in-vitro transcriptional profiling, short-term rodent PK/PD and functional assays, then carefully designed long-term toxicology (including carcinogenicity) if short-term data are encouraging. All work should follow institutional animal-care and regulatory standards. PMC+1
9. Where can I find the primary literature?
Key open-access items: SLU-PP-332 mechanistic/rodent studies (Billon et al., PMC 2024) and reviews of GW-501516/PPARδ biology (Smith et al., PMC 2016). Links are provided in the references above. PMC+1
10. Is it ever safe to use these together in humans?
Not outside tightly controlled, ethically approved clinical trials. Cardarine’s carcinogenic signal and the absence of robust human safety data for SLU-PP-332 make casual or off-label human experimentation unsafe and ill-advised. Regulatory and anti-doping bodies have issued warnings. PMC+1
Final notes & responsible-use disclaimer
This document is for preclinical research and educational purposes only. It does not provide dosing, administration, or protocol instructions for human use.
