Research Overview

SLU-PP-332 is a small-molecule pan-agonist of the estrogen-related receptors (ERRα, ERRβ, ERRγ), a family of orphan nuclear receptors that sit at the master-regulator level of mitochondrial biogenesis, oxidative phosphorylation and fatty-acid utilization. Unlike caffeine, β-agonists or thyroid analogues, SLU-PP-332 carries no central stimulant activity and does not modulate appetite — it works exclusively through transcriptional reprogramming of metabolic gene expression in skeletal muscle, heart and adipose tissue. In Billon et al. (2023, Nature), four weeks of oral dosing in mice increased treadmill running distance by ~70 %, expanded type-IIa oxidative fibers, and elevated mitochondrial content even in sedentary animals. Subsequent work has demonstrated activity against diet-induced obesity, hepatic steatosis and heart-failure models, positioning SLU-PP-332 as the lead chemical probe for the entire ERR-PGC-1α axis.

Primary Research Areas

• ERRα / ERRβ / ERRγ pharmacology: the only well-characterized small molecule that engages all three ERR isoforms in a physiologically meaningful dose range, enabling clean dissection of nuclear-receptor-driven transcription.
• Mitochondrial biogenesis and oxidative capacity: used to probe PGC-1α-coordinated upregulation of TCA-cycle enzymes, electron-transport-chain components and fatty-acid β-oxidation machinery in skeletal muscle and cardiomyocytes.
• Exercise-mimetic phenotypes: the reference tool for studying transcriptional adaptations of endurance training in sedentary models, including fiber-type shifting toward oxidative type-IIa.
• Metabolic disease models: investigated in diet-induced obesity, hepatic steatosis, and insulin-resistance paradigms where it improves systemic substrate utilization without weight loss in lean animals.
• Cardiac energetics and heart failure: evaluated in rodent models of pressure-overload and ischemia-reperfusion, where ERR activation rescues cardiac mitochondrial gene expression and contractile reserve.