Hydroxyl carboxylic acid receptor-2 (HCAR2) as a potential target in neurometabolic diseases.

Hydroxycarboxylic acid receptor 2 (HCAR2) is a G-protein-coupled receptor initially identified for its role in lipid metabolism. Beyond its classical metabolic functions, HCAR2 plays a pivotal role in chronic inflammatory diseases, neurometabolic disorders, and pain modulation. Evidence from preclinical studies suggest that when endogenously activated by β-hydroxybutyrate and pharmacologically by niacin and its derivatives, HCAR2 attenuates microglial reactivity, suppress pro-inflammatory cytokine release, and modulate neuronal excitability, by offering neuroprotective benefits in neurological disorders and chronic pain. Additionally, emerging data highlight its involvement in gut-brain axis regulation, linking dietary interventions and microbiota-derived metabolites to Central Nervous System function. The development of selective HCAR2 agonists with improved pharmacokinetic and safety profiles holds promise for treatments targeting both peripheral and central pathologies. This review explores the structural and functional aspects of HCAR2, and describe novel synthetic HCAR2 agonists, by emphasizing its therapeutic potential across a spectrum of metabolic and neuroinflammatory disorders.