Retinoic acid receptor-related Orphan Receptor (ROR) (ROR)

Retinoic acid receptor-related Orphan Receptors (RORs) are a subfamily of the nuclear receptor superfamily of transcription factors, comprising three members: RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3) (UniProt P35398, Q92753, P51449). These receptors function as ligand-dependent transcription factors that regulate diverse physiological processes, including the circadian rhythm, immune system development, and metabolic homeostasis (Frontiers in Endocrinology, 2021). RORγt, a specific isoform of RORγ, is the master regulator of Th17 cell differentiation and the production of pro-inflammatory cytokines like IL-17, making it a high-priority target for autoimmune and inflammatory diseases such as psoriasis and rheumatoid arthritis (Nature Reviews Drug Discovery, 2021). RORα is involved in cerebellar development and lipid metabolism, while RORβ is primarily expressed in the central nervous system and retina, influencing circadian behavior and sensory processing (Wikipedia). Therapeutic strategies targeting RORs include the development of inverse agonists to suppress Th17-mediated inflammation and agonists to enhance anti-tumor immunity or treat metabolic disorders (Expert Opinion on Drug Discovery, 2021). Despite their therapeutic potential, clinical development of RORγt inhibitors has faced challenges, including safety concerns such as thymic toxicity and hepatotoxicity (ResearchGate).

Other names

Retinoid-related orphan receptorNR1FROR familyNuclear receptor subfamily 1 group F

RORs function as ligand-dependent transcription factors that bind to ROR response elements (ROREs) in the regulatory regions of target genes. Drugs targeting RORs, particularly RORγt inverse agonists, bind to the ligand-binding domain and stabilize an inactive conformation that prevents the recruitment of co-activators and promotes the binding of co-repressors, thereby inhibiting the transcription of pro-inflammatory cytokines like IL-17A and IL-17F.