GPT5 Deep Research:
Summary of PubMed Studies Discussing SLU‑PP‑332
Introduction
SLU‑PP‑332 is a synthetic estrogen‑related receptor (ERR) agonist developed to mimic some of the metabolic and mitochondrial effects of physical exercise. ERRs are nuclear receptors (ERRα, ERRβ and ERRγ) that regulate genes involved in energy metabolism. Because these receptors are constitutively active transcription factors, identifying small‑molecule agonists with suitable pharmacokinetics has been challenging. SLU‑PP‑332 was initially described in 2023 as a pan‑ERR agonist with high potency for ERRα. Since then, several studies have evaluated its biological effects in various models of metabolic disease, heart failure, kidney aging and muscle physiology.
The following sections summarise every PubMed‑indexed article that investigates or references SLU‑PP‑332 (as of 2025). For each study, the objective, methods, key results and conclusions are summarised, with citations to the relevant parts of the source articles.
Synthetic ERRα/β/γ Agonist Induces an ERRα‑Dependent Acute Aerobic Exercise Response (Billon et al., 2023)
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Objective – Identify and characterise a synthetic agonist for the ERR family that can act as an in vivo exercise mimetic.
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Methods – The authors used structure‑based design to develop SLU‑PP‑332, a small‑molecule agonist targeting ERRα/β/γ, with the highest potency for ERRα. Pharmacokinetic properties were assessed to ensure suitability for in vivo use. In vitro experiments examined mitochondrial function and cellular respiration in C2C12 myoblasts. Mice were treated with SLU‑PP‑332 and analysed for muscle fibre composition, running endurance and gene expression patterns.
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Key findings:
- SLU‑PP‑332 has sufficient pharmacokinetic properties to be used as an in vivo tool and increases mitochondrial function and cellular respiration in skeletal muscle cellspubmed.ncbi.nlm.nih.gov.
- In mice, SLU‑PP‑332 increased the proportion of type IIa oxidative muscle fibres and enhanced running endurancepubmed.ncbi.nlm.nih.gov.
- Transcriptomic analyses showed that SLU‑PP‑332 induced an acute aerobic exercise gene program that depended on ERRα activation; ERRα activation was necessary for the improvement in endurancepubmed.ncbi.nlm.nih.gov.
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Conclusion – SLU‑PP‑332 is a first‑in‑class pan‑ERR agonist that induces an acute aerobic exercise response and improves exercise capacity in mice through an ERRα‑dependent mechanism. The study demonstrates the feasibility of targeting ERRα to develop exercise mimetics for metabolic disorders or muscle dysfunction.
A Synthetic ERR Agonist Alleviates Metabolic Syndrome (Billon et al., 2024)
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Objective – Evaluate whether pharmacological activation of ERRs with SLU‑PP‑332 can reproduce exercise‑like metabolic benefits in mouse models of obesity and metabolic syndrome.
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Methods – Diet‑induced obese (DIO) and leptin‑deficient (ob/ob) mice were treated with SLU‑PP‑332. Metabolic parameters, including energy expenditure, fatty‑acid oxidation, fat mass, glucose homeostasis and liver lipids, were assessed.
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Key findings:
- SLU‑PP‑332 administration mimicked exercise‑induced benefits by increasing energy expenditure and fatty‑acid oxidation and reducing fat mass accumulationpubmed.ncbi.nlm.nih.gov.
- The compound decreased obesity and improved insulin sensitivity in models of metabolic syndromepubmed.ncbi.nlm.nih.gov.
- In chow‑fed mice, SLU‑PP‑332 did not significantly improve glucose metabolismpubmed.ncbi.nlm.nih.gov.
- Figures showed that SLU‑PP‑332 improved muscle function, increased fatty‑acid metabolism and energy expenditure, and reduced adipocyte size and liver triglycerides in DIO and ob/ob micepubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov.
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Conclusion – Pharmacological activation of ERRs with SLU‑PP‑332 produces exercise‑like metabolic adaptations, decreasing fat mass and improving insulin sensitivity in obese mice. These results suggest that ERR agonists could be developed as therapeutics for obesity and metabolic syndromepubmed.ncbi.nlm.nih.gov.
Novel Pan‑ERR Agonists Ameliorate Heart Failure (Xu et al., 2024)
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Objective – Determine whether pan‑ERR agonists, including SLU‑PP‑332 and the newly synthesised SLU‑PP‑915, can protect against pressure overload–induced heart failure (HF).
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Methods – Using structure‑based design, the authors developed two structurally distinct pan‑ERR agonists (SLU‑PP‑332 and SLU‑PP‑915). Mice underwent transverse aortic constriction (TAC) to induce HF and were treated with vehicle, SLU‑PP‑332 or SLU‑PP‑915 for six weeks. Cardiac function, fibrosis, survival, metabolomics and transcriptomics were analysed. Genetic dependency experiments in vitro and in vivo examined the contribution of specific ERR isoforms.
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Key findings:
- Both SLU‑PP‑332 and SLU‑PP‑915 significantly improved ejection fraction, reduced fibrosis and increased survival in the pressure overload modelpubmed.ncbi.nlm.nih.gov.
- The agonists activated a broad spectrum of metabolic genes, particularly those involved in fatty‑acid metabolism and mitochondrial functionpubmed.ncbi.nlm.nih.gov.
- Metabolomics showed that ERR agonists normalised metabolic profiles related to fatty acids and oxidative phosphorylationpubmed.ncbi.nlm.nih.gov.
- Increased mitochondrial oxidative capacity and fatty‑acid utilisation were observed both in vivo and in vitro; genetic experiments indicated that ERRγ mediates most of the transcriptional response and cardioprotective effectspubmed.ncbi.nlm.nih.gov.
- ERR agonism downregulated cell cycle and development pathways partly via E2F1 in cardiomyocytespubmed.ncbi.nlm.nih.gov.
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Conclusion – Activation of ERRs with SLU‑PP‑332 or SLU‑PP‑915 preserves oxidative metabolism and confers cardioprotection in pressure overload–induced HF. ERRγ appears to be the principal isoform mediating these benefits, highlighting pan‑ERR agonists as promising candidates for HF therapypubmed.ncbi.nlm.nih.gov.
Estrogen‑Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney (Tran et al., 2023)
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Objective – Investigate whether a pan‑ERR agonist can reverse age‑related mitochondrial dysfunction and inflammation in the kidney.
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Methods – Aging human and mouse kidneys were examined for expression of ERRs. Twenty‑one‑month‑old mice were treated with SLU‑PP‑332 for eight weeks. Another group received the stimulator of interferon genes (STING) inhibitor C‑176 for three weeks. Albuminuria, podocyte loss, mitochondrial function and inflammatory cytokines were measured.
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Key findings:
- ERRα and ERRγ expression decreased in aging kidneys but was preserved in mice under lifelong caloric restrictionpubmed.ncbi.nlm.nih.gov.
- SLU‑PP‑332 treatment for eight weeks reversed age‑related increases in albuminuria, podocyte loss, mitochondrial dysfunction and pro‑inflammatory cytokinespubmed.ncbi.nlm.nih.gov.
- The beneficial effects involved inhibition of the cGAS‑STING and STAT3 signalling pathwayspubmed.ncbi.nlm.nih.gov.
- STING inhibitor C‑176 reversed inflammatory cytokines and senescence markers but unexpectedly decreased PGC‑1α, ERRα and mitochondrial complex expressionpubmed.ncbi.nlm.nih.gov.
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Conclusion – ERR agonism with SLU‑PP‑332 mimics caloric restriction by restoring mitochondrial function and reducing inflammation in the aging kidney. These findings identify ERRs as druggable targets for preventing age‑related renal diseasepubmed.ncbi.nlm.nih.gov.
Development and Pharmacological Evaluation of a New Chemical Series of Potent Pan‑ERR Agonists (Hampton et al., 2023)
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Objective – Improve on the properties of SLU‑PP‑332 by designing new pan‑ERR agonists with better potency and metabolic stability.
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Methods – Structure‑based drug design (SBDD) was used to replace the acyl hydrazide scaffold of SLU‑PP‑332 with a 2,5‑disubstituted thiophene amide core. Analogues were synthesised and tested in ERRγ co‑transfection assays. Selected compounds were assessed for metabolic stability and gene‑expression effects in vitro and in vivo.
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Key findings:
- Figure 2 of the paper provides structure and ERR co‑transfection data for SLU‑PP‑332 (compound 6) and the novel analoguespmc.ncbi.nlm.nih.gov.
- The authors note that SLU‑PP‑332 showed a preference for ERRα; several of the newly developed agonists were potent against all three ERR isoformspmc.ncbi.nlm.nih.gov.
- DDIT4 was previously identified as an ERRα‑specific target gene regulated by SLU‑PP‑332; this gene was included as a marker in assessing new compoundspmc.ncbi.nlm.nih.gov.
- SLU‑PP‑915 (a boronic‑acid analogue) demonstrated improved metabolic stability and was able to up‑regulate ERR target genes such as PGC‑1α, LDHA and PDK4 in cell‑based assays. In vivo, SLU‑PP‑915 increased DDIT4, PDK4 and PGC‑1α expression and enhanced running distance and time in micepmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.
- Compared with SLU‑PP‑332, SLU‑PP‑915 was easier to formulate for in vivo studies and retained strong activity at all three ERR isoformspmc.ncbi.nlm.nih.gov.
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Conclusion – The study provides a new series of ERR agonists with improved pharmacological properties. By comparing to SLU‑PP‑332, the authors demonstrate that modifying the scaffold can enhance potency and metabolic stability while maintaining the ability to mimic exercise phenotypes. SLU‑PP‑915 is highlighted as a promising successor to SLU‑PP‑332pmc.ncbi.nlm.nih.gov.
Targeting ERRs to Counteract Age‑Related Muscle Atrophy Associated With Physical Inactivity (Bonanni et al., 2025)
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Objective – Evaluate whether activating ERRs with SLU‑PP‑332 can mitigate muscle atrophy and oxidative stress in sedentary older women.
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Methods – The study recruited two groups of elderly women: physically active and inactive. Muscle biopsies were taken for histological and western‑blot analyses. Primary myoblast cultures derived from inactive women were treated with SLU‑PP‑332 (10⁻⁵ M for 48 h) and examined for differentiation, oxidative stress and expression of key genes (NOX4, SIRT1, PGC‑1α, ERRα, FNDC5, Akt and Bcl‑2).
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Key findings:
- Inactive subjects showed higher NOX4 and lower SIRT1, PGC‑1α, ERRα and FNDC5 expression compared with active subjectspmc.ncbi.nlm.nih.gov.
- Treatment of myoblasts with SLU‑PP‑332 down‑regulated NOX4 and up‑regulated SIRT1, PGC‑1α, ERRα, FNDC5, Akt and Bcl‑2pmc.ncbi.nlm.nih.gov.
- SLU‑PP‑332 reduced cytotoxicity, oxidative stress and senescence markers while increasing reduced glutathione levelspmc.ncbi.nlm.nih.gov.
- The agonist promoted myotube formation and improved cell differentiation in vitropmc.ncbi.nlm.nih.gov.
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Conclusion – This pilot study suggests that pharmacologic activation of ERRs with SLU‑PP‑332 may counteract molecular markers of muscle atrophy and oxidative stress in sedentary older adults. The authors propose that targeting ERRs could complement exercise to mitigate age‑related muscle decline, although larger studies are neededpmc.ncbi.nlm.nih.gov.
Related Commentary and Reviews
Several commentaries and reviews discuss SLU‑PP‑332 and ERR agonism:
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DDIT4 regulation by SLU‑PP‑332 – The chemical design paper notes that DDIT4, an acute exercise gene, is an ERRα‑specific target regulated by SLU‑PP‑332 and that agonism up‑regulates DDIT4, PDK4 and PGC‑1α expression in vivopmc.ncbi.nlm.nih.gov.
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Comprehensive therapeutics for metabolic syndrome – A commentary in the Journal of Pharmacology and Experimental Therapeutics (Ross, 2024) mentions pharmacological avenues for metabolic syndrome but does not specifically discuss SLU‑PP‑332.
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Other ERR ligands – Earlier work described SLU‑PP‑1072, an ERRα/γ inverse agonist, but this compound does not mention SLU‑PP‑332 and therefore was not summarised.
Overall Perspective and Future Directions
SLU‑PP‑332 has emerged as a promising pharmacological exercise mimetic that activates ERRα/β/γ receptors. Across multiple models, the compound increases mitochondrial function, enhances fatty‑acid oxidation, promotes oxidative muscle fibres and improves endurance. Studies in obese mice demonstrate reductions in fat mass and improvements in insulin sensitivity, whereas experiments in heart failure models show preservation of cardiac function and survival. In aging kidneys, SLU‑PP‑332 reverses mitochondrial dysfunction and inflammation via cGAS‑STING–STAT3 pathways. A small human study suggests that ERR agonism could counteract muscle atrophy associated with inactivity.
However, SLU‑PP‑332 has limitations, including moderate metabolic stability and a bias toward ERRα. Structure‑based design has produced newer agonists such as SLU‑PP‑915 with improved potency and stability. Future research should explore long‑term safety, dose optimisation and potential combinatorial therapies with exercise or other metabolic drugs. Clinical trials will be needed to determine whether ERR agonists can translate into therapeutic interventions for metabolic syndrome, heart failure, kidney disease or sarcopenia in humans.
In summary, PubMed-indexed research on the synthetic estrogen-related receptor agonist SLU‑PP‑332 demonstrates its powerful exercise-mimetic properties across multiple systems. Early work identified SLU‑PP‑332 as a pan-ERR agonist with a strong preference for ERRα, showing that it enhances mitochondrial respiration, shifts muscle fibres toward oxidative type IIa, and induces an ERRα-dependent acute aerobic gene programpubmed.ncbi.nlm.nih.gov. Subsequent studies in obese mice revealed that SLU‑PP‑332 increases energy expenditure, fatty-acid oxidation, and insulin sensitivity while reducing fat mass, thereby alleviating features of metabolic syndromepubmed.ncbi.nlm.nih.gov. These findings suggest pharmacological activation of ERRs could replicate some benefits of physical exercise without actual training.
Looking further afield, SLU‑PP‑332 and the newer analogue SLU‑PP‑915 were shown to protect against pressure-overload-induced heart failure by improving ejection fraction, reducing fibrosis, and normalising cardiac metabolic profilespubmed.ncbi.nlm.nih.gov. In aged kidneys, SLU‑PP‑332 reversed mitochondrial dysfunction and inflammation, mimicking the effects of caloric restrictionpubmed.ncbi.nlm.nih.gov. A small pilot study in sedentary older women demonstrated that SLU‑PP‑332 downregulated oxidative-stress markers and enhanced muscle differentiation in primary myoblast culturespmc.ncbi.nlm.nih.gov. Collectively, these studies indicate that ERR agonism may hold therapeutic potential for metabolic diseases, cardiac and renal dysfunction, and age-related muscle atrophy; however, the limited human data and the need for improved pharmacokinetics emphasise the importance of ongoing development and rigorous clinical testing.
