The cardiac exercise mimetic — a different pathway entirely
SLU-PP-332 was identified by Bharat Bhatt's laboratory at the University of Southern California in 2023 as part of a systematic screen for agonists of estrogen-related receptors (ERRα and ERRγ). ERRs are nuclear receptors — transcription factors that sit inside cells and directly control gene expression programmes involved in mitochondrial biogenesis, fatty acid oxidation, and cardiac energy metabolism. ERRα and ERRγ are the dominant drivers of the gene expression changes that appear in the heart after endurance training.
When SLU-PP-332 was administered to sedentary mice, it activated cardiac ERRα/γ and produced the same gene expression signature — and the same structural cardiac adaptations — normally only seen in trained athletes. The hearts of treated sedentary animals showed increased mitochondrial density, improved oxidative capacity, and resistance to age-related cardiac decline. These are not just metabolic measurements — they are architectural changes to the heart itself.
The distinction from AICAR is important: AICAR works by activating AMPK (the cellular energy sensor) and producing a broad metabolic exercise-mimetic effect across multiple tissues. SLU-PP-332 works directly at the nuclear receptor level in cardiac tissue — a fundamentally different mechanism that operates in the nucleus rather than the cytoplasm, and with more cardiac specificity than AICAR's broad metabolic effects.
Why ERRα/γ matters for cardiac ageing: ERRα/γ activity declines with age in cardiac tissue — contributing to the age-related reduction in cardiac oxidative capacity, mitochondrial function, and exercise tolerance that characterises cardiovascular ageing. SLU-PP-332 essentially switches back on the transcriptional programmes that age switches off. Whether this translates into clinically meaningful cardiac protection in humans is the central open question.
Nuclear receptor activation — gene programmes, not enzymes
How SLU-PP-332 Works
The gaps in the evidence
SLU-PP-332 was published in a single 2023 paper and has very limited follow-up research. Critical unknowns: human pharmacokinetics (the compound was only studied in mice), off-target effects of ERR agonism in non-cardiac tissues (ERRs are expressed in liver, adipose, and reproductive tissue), optimal dosing for cardiac vs metabolic effects, safety at chronic high doses, whether the cardiac structural changes are stable or revert after discontinuation, and whether the effects extend beyond cardiac tissue to skeletal muscle endurance.
The community has largely not adopted SLU-PP-332 yet — partly because it is too new, partly because it is a small molecule rather than a peptide (though it is often discussed in peptide circles), and partly because synthesis of verified SLU-PP-332 from research chemical suppliers is currently limited. This will likely change as the research matures and the compound becomes more widely available through research channels.
Follow-up publications from the Bhatt laboratory at USC. Any extension to human studies (Phase 1 safety trials would be the next step). WADA monitoring — if the compound reaches human trials and demonstrates performance enhancement, it will likely be added to the prohibited list (as AICAR was rapidly after its 2008 characterisation). Skeletal muscle data — does the cardiac ERR activation translate to skeletal muscle endurance improvements?