RAR-related orphan receptor-gamma (ROR-gamma) (ROR-gamma)

RAR-related orphan receptor-gamma (ROR-gamma) is a member of the nuclear receptor family of transcription factors, encoded by the RORC gene [2, 3]. It exists in two primary isoforms: RORγ1, which is expressed in various tissues like the liver and muscle to regulate metabolism and circadian rhythms, and RORγt, which is specifically expressed in immune cells [1, 5]. RORγt serves as the master regulator for the differentiation of T helper 17 (Th17) cells and the production of pro-inflammatory cytokines such as IL-17A and IL-17F [4, 11]. Due to its central role in the Th17 pathway, ROR-gamma is a major therapeutic target for autoimmune and inflammatory diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis [4, 8]. Pharmacological modulation typically involves inverse agonists that inhibit RORγt activity to reduce inflammation, while agonists are being investigated for their potential to enhance anti-tumor immunity in oncology [2, 12]. However, targeting ROR-gamma carries potential safety risks, such as the disruption of thymocyte development and the theoretical risk of thymic lymphoma, as observed in ROR-gamma-deficient mouse models [1, 9].

Other names

RORCNR1F3RORGRZR-GAMMARZRGTORIMD42RAR-related orphan receptor C

Drugs targeting ROR-gamma primarily function as inverse agonists or agonists. Inverse agonists bind to the ligand-binding domain (LBD), inducing a conformational change that destabilizes Helix 12 (AF2), which leads to the displacement of transcriptional coactivators (e.g., SRC1, SRC2) and the recruitment of corepressors (e.g., NCoR, SMRT) [4, 9, 12, 13]. This repression inhibits the transcription of pro-inflammatory genes, such as IL17A and IL17F, thereby suppressing Th17 cell differentiation and activity [1, 11]. Conversely, ROR-gamma agonists stabilize the active conformation of the receptor, promoting coactivator recruitment and enhancing the expression of target genes to stimulate immune responses, particularly in the context of cancer immunotherapy [2, 12]. The modulation of ROR-gamma activity thus provides a mechanism to fine-tune the balance between pro-inflammatory and regulatory immune responses [1, 5].