SLU-PP-332

The estrogen-related receptors are orphan nuclear receptors, not receptors for estrogen. Genetic studies show they matter for muscle's capacity for exercise, but ERRα had proved hard to activate with a drug. SLU-PP-332, from Saint Louis University, targets all three ERRs with the highest potency at ERRα, and works well enough in vivo to be used as a research tool [1].

The mouse results are what made it famous. It increased the proportion of oxidative type IIa muscle fibres and improved endurance [1]. In diet-induced obese and ob/ob mice it raised energy expenditure and fatty acid oxidation, reduced fat mass and improved insulin sensitivity [2]. In a pressure-overload heart failure model it improved ejection fraction, reduced fibrosis and increased survival, mainly through ERRγ [3]. In 21-month-old mice, eight weeks of treatment reversed age-related albuminuria, podocyte loss, mitochondrial dysfunction and kidney inflammation [4].

The ERRs control genes for mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation and the Krebs cycle [5]. Activating them with SLU-PP-332 set off an acute aerobic exercise program in muscle that depended on ERRα [1]. It induced the exercise gene Ddit4 as strongly as treadmill running or more [5]. In the heart its benefit ran mainly through ERRγ, which drove fatty acid metabolism and mitochondrial function [3].

Chemically it is an acyl hydrazone. A 2026 structure-activity study mapped which parts of the scaffold control potency and ERRα versus ERRγ activity [6].

There is no human safety data. A 2026 systematic review of the animal studies reported no evident toxicity in obesity models, and concluded that clinical trials are needed to establish efficacy and safety in humans [7].

It is not orally bioavailable in mice [5], so oral products sold online may deliver little. Their contents are unverified in any case.

The World Anti-Doping Agency prohibits exercise mimetics and metabolic modulators in sport. Anti-doping laboratories have already mapped SLU-PP-332's metabolites in human liver preparations so they can detect it [8][9].

No interaction studies exist. In human liver preparations it forms six phase I and three phase II metabolites [9], but no study says which enzymes are involved.