Key findings
- The compound activates all three estrogen-related receptor subtypes with the highest potency at the alpha subtype, which the authors note had been difficult to reach with earlier designs that targeted the beta and gamma subtypes. [1]
- In a skeletal muscle cell line the compound raised mitochondrial function and cellular respiration, and in mice it increased type IIa oxidative muscle fibers and endurance in a manner that required the alpha subtype. [1]
- In a pressure overload rodent model of cardiac failure, transcriptomic and metabolomic profiling showed activation of fatty acid metabolism and mitochondrial genes, and genetic dependency experiments identified the gamma subtype as the mediator. [2]
- In 21-month-old mice an eight-week course reversed age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines through the cyclic GMP-AMP synthase, STING and STAT3 pathways. [3]
Identity and structure
- Receptor targets
- A pan agonist of the estrogen-related receptors alpha, beta and gamma, a family of orphan nuclear receptors, with highest potency at the alpha subtype [1]
- Related compound
- SLU-PP-915 is a structurally distinct pan agonist designed alongside this compound in the same structure-based programme; it is a different material [2]
- Design basis
- Produced by a structure-based design approach aimed at agonists whose pharmacokinetic properties permit in vivo use [1][2]
- Form as supplied
- Solid; the counterion is not stated in the cited work
Mechanism as studied
The identification report frames the compound as a tool rather than a single-target ligand. Earlier designs had produced beta and gamma subtype agonists while the alpha subtype resisted agonist design, and this compound reaches all three with the alpha subtype most potently, which the authors then use to ask which subtype the cellular and animal observations depend on. [1]
Subtype dependency is answered differently in different tissues. In muscle, activation of the alpha subtype was critical for the endurance change and for the acute aerobic gene program; in heart, genetic dependency experiments run both in cells and in animals identified the gamma subtype as the main mediator of the transcriptional regulation and of the cardiac observations, alongside a downregulation of cell cycle and development pathways partially mediated by E2F1 in cardiomyocytes. [1][2]
Kidney work places the receptors upstream of an inflammatory pathway: the receptors declined in aging mouse kidney and were preserved by lifelong caloric restriction, and agonist treatment reversed the age-related changes through the cyclic GMP-AMP synthase, STING and STAT3 signaling pathways, with a STING inhibitor reproducing part of the pattern. [3]
Research findings
In vitro
- System
- Receptor assays covering the estrogen-related receptor alpha, beta and gamma subtypes, and a skeletal muscle cell line
- Measured
- Agonist potency at each subtype, mitochondrial function and cellular respiration
- Reported
- All three subtypes were activated with the highest potency at the alpha subtype, and mitochondrial function and cellular respiration increased in the muscle cell line. [1]
Preclinical in vivo
- System
- Mice, including animals used to test dependence on the alpha subtype
- Measured
- Type IIa oxidative skeletal muscle fiber proportion, exercise endurance and the acute aerobic gene program
- Reported
- Type IIa fibers and endurance increased, an alpha-subtype-specific acute aerobic gene program was induced, and alpha subtype activation was critical for the endurance change. [1]
Preclinical in vivo
- System
- Diet-induced obese mice and ob/ob mice
- Measured
- Energy expenditure, fatty acid oxidation, fat mass accumulation and insulin sensitivity
- Reported
- Energy expenditure and fatty acid oxidation increased, fat mass accumulation decreased, and insulin sensitivity improved in the metabolic syndrome models. [4]
Preclinical in vivo
- System
- 21-month-old mice over eight weeks, compared with lifelong caloric restriction and with a STING inhibitor course in the same age group
- Measured
- Albuminuria, podocyte loss, mitochondrial function, inflammatory cytokines, and PGC-1 alpha, receptor and mitochondrial complex expression
- Reported
- The age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction and inflammatory cytokines were reversed via cyclic GMP-AMP synthase, STING and STAT3 signaling; the STING inhibitor also reversed the cytokine and senescence marker increases and unexpectedly the declines in PGC-1 alpha and mitochondrial complexes. [3]
Preclinical in vivo
- System
- Mouse pressure overload model of cardiac failure, with RNA sequencing, metabolomics and genetic dependency experiments; a second pan agonist was tested in parallel
- Measured
- Ejection fraction, fibrosis, survival, cardiac hypertrophy, transcript and metabolite profiles, and subtype dependency
- Reported
- Ejection fraction improved and fibrosis was reduced without a change in cardiac hypertrophy; fatty acid metabolism and mitochondrial genes were transcriptionally activated, metabolite profiles normalized, and the gamma subtype was identified as the main mediator. [2]
In vitro
- System
- Primary myoblast cultures established from human skeletal muscle biopsy tissue, and myotubes differentiated from them over 15 days
- Measured
- NOX4, SIRT1, PGC-1 alpha, receptor alpha, FNDC5, Akt and Bcl-2 expression, cytotoxicity, oxidative stress, senescence, reduced glutathione and myotube formation
- Reported
- NOX4 expression fell while SIRT1, PGC-1 alpha, receptor alpha, FNDC5, Akt and Bcl-2 rose; cytotoxicity, oxidative stress and senescence markers decreased, reduced glutathione increased, and myotube formation was abundant. [5]
Handling for in-vitro work
- Comparators in the cited work
- The cardiac report runs this compound alongside the structurally distinct pan agonist SLU-PP-915, so the identity of the agonist used belongs in the method record [2]
- Subtype controls
- The cited work resolves subtype dependency with genetic experiments rather than with the agonist alone, so a subtype-selective control belongs with any new receptor assay [1][2]
- Storage
- Solid material kept dry, dark and cold; solutions prepared fresh and used promptly
Open questions
- The cited work assigns the muscle observations to the alpha subtype and the cardiac observations to the gamma subtype, and does not establish what determines which subtype dominates in a given tissue.
- One cited report is described by its authors as a pilot study with small groups, so the myoblast culture findings it reports are not established on their own.
- The cited work does not report the counterion or salt form, so the nominal mass of a supplied material cannot be checked against these papers.
Lot records
Check the record for the exact material you order. A published paper and a batch certificate answer different questions.
No published lot is available for this exact compound name.
Read a certificate of analysis ↗References
- 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.
- Xu W, Billon C, Li H, et al. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function. Circulation. 2024.
- Wang XX, Myakala K, Libby AE, et al. Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney. The American journal of pathology. 2023.
- Billon C, Schoepke E, Avdagic A, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. The Journal of pharmacology and experimental therapeutics. 2024.
- Bonanni R, Falvino A, Matticari A, et al. Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study. Frontiers in physiology. 2025.
Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.