Hydroxycarboxylic Acid Receptor 2 (GPR109A) and retinopathies: Pathways and Prospects

Abstract

GPR109A, also known as the hydroxycarboxylic acid receptor 2 (HCAR2), is a G protein–coupled receptor with emerging significance in ocular health. Although considerable attention has focused on its role in the diabetic retina, growing evidence suggests that GPR109A may also play an important role in other retinal pathologies, including hypertensive retinopathy (HR) and retinopathy of prematurity (ROP), where inflammation, oxidative stress, and vascular instability similarly drive disease progression. Expressed in key retinal cell types, including retinal pigment epithelial cells, endothelial cells, and microglia, GPR109A mediates anti-inflammatory, antioxidant, and barrier-protective effects through activation by endogenous ligands such as niacin, β-hydroxybutyrate (BHB), and butyrate, as well as synthetic agonists, including monomethyl fumarate (MMF) and L-2-oxothiazolidine-4-carboxylic acid (OTC). This review highlights the broader therapeutic potential of targeting GPR109A across multiple retinal diseases, emphasizing early-stage intervention and opportunities for non-invasive treatment strategies. We also discuss the efficacy and limitations of GPR109A agonists, including those that activate both GPR109A-dependent and receptor-independent pathways, and explore the potential of biased agonism to reduce systemic side effects such as cutaneous flushing. While preclinical data are compelling, further studies are needed to optimize delivery methods, validate efficacy in clinical settings, and overcome translational challenges. Overall, GPR109A represents a promising frontier in the development of preventive therapies for vision-threatening retinal disorders, extending well beyond diabetic retinopathy to conditions such as HR and ROP.