AICAR

What Is AICAR?

AICAR (5-aminoimidazole-4-carboxamide ribonucleotide, also called acadesine) is a small molecule, not a peptide. It is a cell-permeable nucleoside that, once inside the cell, is phosphorylated by adenosine kinase into ZMP, a structural mimic of AMP. ZMP allosterically activates AMPK (AMP-activated protein kinase), the cell's master fuel-sensing enzyme, without actually changing the cellular AMP/ATP ratio. The cell responds as though its energy reserves were depleted and shifts metabolism from storage toward oxidation.

Downstream of AMPK activation, acetyl-CoA carboxylase is phosphorylated and inhibited, which relieves malonyl-CoA inhibition of CPT1 and unlocks fatty-acid transport into mitochondria; GLUT4 translocates to the skeletal-muscle membrane and takes up glucose independently of insulin; PGC-1alpha is induced and drives mitochondrial biogenesis; and mTOR is suppressed while autophagy rises. The signature finding came from Narkar, Downes, Evans, and colleagues in Cell (2008), where sedentary mice treated with AICAR for four weeks gained 44% treadmill endurance over untreated controls without training. That paper produced the exercise-mimetic label and led to AICAR's addition to the WADA prohibited list in 2011.

As acadesine, the compound has formal human clinical history in cardiac ischaemia-reperfusion trials (RED-CABG, ACTT-CABG, Phase 3 in coronary bypass surgery), where intravenous infusion reduced infarct size but did not meet the primary endpoint. No human trials in metabolic or performance contexts exist.