RAR-related orphan receptor gamma (specifically, the thymus-specific isoform RORγt) (RORγt)

RAR-related orphan receptor gamma (RORγ), encoded by the RORC gene, is a nuclear hormone receptor and transcription factor with two main isoforms: the broadly expressed RORγ and the immune/lymphoid-restricted RORγt. RORγt functions as a master regulator of Th17 cell differentiation and type 3 innate lymphoid cell identity, orchestrating gene programs that drive antimicrobial host defense, influence the development of secondary lymphoid tissues, and mediate the IL-17/IL-23 inflammatory axis. Ligand binding (notably by oxysterols or synthetic inhibitors) modulates its gene regulatory activity, making RORγt a strategic therapeutic target in autoimmunity, cancer, and inflammation. Pharmacological inhibition of RORγt mitigates autoimmune and inflammatory pathology by blocking pro-inflammatory cytokine production, but also confers infection risk due to the essential role of Th17/ILC3 immunity.

Other names

RORγROR gammaRAR-related orphan receptor gammaRORCNR1F3RORgammaRetinoic acid-related orphan receptor gammaRORγ1 (long isoform)RORγ2 (isoform t)

Inhibition (inverse agonism) of RORγt blocks transcription of Th17-signature cytokines (IL-17A, IL-17F, IL-22) and reduces pathogenic Th17 cell differentiation. Agonists/oxysterols promote coactivator recruitment and nuclear transactivation of target genes in Th17 and ILC3 lineages. Inverse agonists destabilize helix 12 of the ligand binding domain and induce conformational changes that reduce gene activation.