HCAR2 is a G-protein-coupled receptor that functions as a high-affinity receptor for both nicotinic acid (niacin) and the ketone body β-hydroxybutyrate (BHB) 1. Upon activation, HCAR2 mediates Gi-protein-coupled signaling that inhibits adenylyl cyclase, reducing cAMP levels and promoting increased adiponectin secretion while decreasing lipolysis [UniProt]. HCAR2 also facilitates nicotinic acid-induced apoptosis in mature neutrophils through cAMP reduction and altered protein kinase A activity [UniProt]. Beyond lipid metabolism, HCAR2 activation by BHB demonstrates significant disease-relevant functions. BHB-HCAR2 signaling suppresses colorectal cancer growth by inducing the transcriptional regulator Hopx, thereby reducing colonic crypt cell proliferation 2. In neuroinflammatory contexts, niacin engages HCAR2 to regulate immune responses and facilitate phagocytosis of myelin debris and amyloid-beta, suggesting therapeutic potential in multiple sclerosis and Alzheimer's disease 3. Clinically, HCAR2 represents a promising therapeutic target for cardiovascular and neuroinflammatory diseases 1. However, niacin therapy commonly produces flushing side-effects, prompting development of alternative HCAR2 agonists with improved tolerability 1. Recent structural characterization of HCAR2-ligand complexes has revealed allosteric modulation mechanisms that may enable next-generation therapeutics with reduced side-effects while maintaining efficacy 1.