SLU-PP-332

SLU-PP-332 is a synthetic small molecule that switches on all three estrogen-related receptors, ERR alpha, ERR beta and ERR gamma: orphan nuclear receptors that control genes for mitochondrial biogenesis, oxidative phosphorylation and fatty acid oxidation. Chemists at Saint Louis University and the Center for Clinical Pharmacology built it from the older agonist GSK4716, adding a naphthalene group for potency at ERR alpha.

In cell reporter assays its half maximal effective concentration was 98 nanomolar at ERR alpha, 230 at ERR beta and 430 at ERR gamma, with no activity at the classical estrogen receptors (Billon et al., 2023). It is not a peptide: no amino acids, no peptide bonds.

Published work falls into six areas, each named with its model. It is all preclinical: rodents, cells and analytical chemistry, with no human trial indexed in PubMed.

Design and receptor activity

The scaffold came first: a 2020 paper reworked GSK4716 into pan agonists active at ERR alpha that raised PGC-1 alpha and PDK4 messenger RNA (Shahien et al., 2020). SLU-PP-332 came from the same effort, its naphthalene group aimed at a phenylalanine residue unique to ERR alpha, with binding confirmed by limited proteolysis and scanning fluorimetry (Billon et al., 2023). A 2026 review calls it an outstanding pan-agonist among the acyl hydrazones and notes the metabolic liability of that chemotype (Radwan et al., 2026). Models: transfected cells and receptor domains.

Skeletal muscle, mitochondria and exercise-response genes

In C2C12 mouse myoblasts, 24 hours of exposure raised maximum mitochondrial respiration and the ERR target gene PDK4. Male C57BL/6J mice that received 50 mg/kg twice daily by intraperitoneal injection held more oxidative type IIa fibers in the quadriceps, and sedentary animals ran longer on a treadmill than vehicle controls.

The gene raised most was Ddit4, a driver of the acute aerobic exercise program: one 50 mg/kg amount raised it about threefold, against about sixfold for a 40 minute run. In myocytes and mice lacking ERR alpha in muscle, both effects were lost (Billon et al., 2023). Models: mouse myoblasts, primary myocytes, knockout mice.

Mouse models of obesity and metabolic syndrome

Diet-induced obese mice and ob/ob mice received 50 mg/kg twice daily by intraperitoneal injection for 28 and 12 days. In chow-fed mice the respiratory exchange ratio fell within two hours of the first amount and stayed low, and it was also lower in the diet-induced group, pointing to a shift toward fatty acid oxidation; energy expenditure rose, food intake held steady, fat mass gain was about 0.5 g against about 5 g in vehicle controls, body weight was about 12 percent lower at day 28, and fasting glucose and insulin were lower.

In lean chow-fed mice the same schedule changed neither glucose tolerance nor islet structure (Billon et al., 2024). Models: obese and chow-fed male mice.

Heart failure and autophagy models

In mice given transverse aortic constriction, a pressure overload model of heart failure, 25 mg/kg twice daily for six weeks held ejection fraction above vehicle controls, cut fibrosis and raised survival, while leaving cardiac hypertrophy unchanged. RNA sequencing showed broad activation of fatty acid and oxidative phosphorylation genes, and knockdown plus knockout work pointed to ERR gamma as the main mediator (Xu et al., 2024). A follow-up found that ERR activation raises transcription factor EB, master regulator of autophagy, in rat ventricular myocytes and C2C12 cells (Losby et al., 2024). Models: mouse surgery, rat cardiomyocytes, myoblasts.

Aging kidney and human muscle cells

Male C57BL/6 mice aged 21 months received 25 mg/kg per day for eight weeks. Albuminuria, podocyte loss, mitochondrial damage on electron microscopy and inflammatory cytokine expression all moved back toward young-mouse values, through cyclic GMP-AMP synthase, STING and STAT3 signaling (Wang et al., 2023).

The one study of its effects on human cells is small: primary myoblasts from 10 inactive women undergoing hip arthroplasty sat in 10 micromolar SLU-PP-332 for 48 hours, after which NOX4 fell, SIRT1, PGC-1 alpha, ERR alpha and FNDC5 rose, and myotube formation increased (Bonanni et al., 2025). Those were cultured cells, not people.

Chemical limits, metabolism and doping-control analysis

Two 2026 papers set the ceiling: a structure-activity study measured kinetic solubility of 0.2 micromolar and a human liver microsome half-life of 31.3 minutes (Okda et al., 2026), and work on SLU-PP-915 states plainly that SLU-PP-332 lacks oral bioavailability (Billon et al., 2026).

Two sports-testing laboratories published detection methods: a UCLA group mapped 22 metabolites in human liver S9 fractions (Avliyakulov et al., 2026), and a German group characterised both compounds by high-resolution mass spectrometry (Möller et al., 2026). Models: in vitro liver fractions.