Hcar2, also known as GPR109A, is a hydroxycarboxylic acid receptor. It is modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, and activates Gi/o protein or β -arrestin effectors. HCAR2 is involved in various pathophysiological events and is a promising therapeutic target for inflammation-related diseases, neurological disorders, and metabolic diseases [1,3,4].

In a 5xFAD mouse model of Alzheimer's disease, genetic inactivation of Hcar2 led to impairment of the microglial response to amyloid deposition, exacerbating amyloid burden, neuronal loss, and cognitive deficits. Conversely, activation of HCAR2 with an FDA-approved niacin formulation reduced plaque burden, neuronal dystrophy, and rescued working memory deficits, indicating its crucial role in microglial response to amyloid pathology [2]. In osteoarthritis, β-hydroxybutyrate enhanced chondrocyte mitophagy and reduced cartilage degeneration through the HCAR2/AMPK/PINK1/Parkin pathway, and this protective effect was lost when HCAR2 was knocked down [5]. In colorectal cancer, β-hydroxybutyrate acts through Hcar2 to suppress intestinal tumour growth [6].

In conclusion, Hcar2 plays essential roles in multiple biological processes and diseases. Gene knockout mouse models have revealed its importance in microglial response in Alzheimer's disease, chondrocyte protection in osteoarthritis, and tumour suppression in colorectal cancer. These findings highlight its potential as a therapeutic target for related diseases.