Retinoic acid receptor-related orphan receptor gamma (RORγ) (RORγ)

Retinoic acid receptor-related orphan receptor gamma (RORγ) is a member of the nuclear receptor superfamily that acts as a ligand-dependent transcription factor [UniProt P51449, Jetten 2009]. It exists in two main isoforms: RORγ1, which is expressed in various tissues like muscle and liver, and RORγt, which is exclusively expressed in the immune system [NCBI Gene 6097, Ivanov 2006]. RORγt is recognized as the master regulator for the differentiation of T helper 17 (Th17) cells, which produce pro-inflammatory cytokines such as IL-17A and IL-22 [Ivanov 2006, Cua 2010]. These cytokines play a pivotal role in the defense against extracellular pathogens but are also central to the pathogenesis of autoimmune diseases like psoriasis and rheumatoid arthritis [Cook 2015, Cua 2010]. Therapeutic strategies often involve small molecule inverse agonists that bind to the RORγ ligand-binding domain, preventing the recruitment of co-activators and thereby suppressing the expression of inflammatory genes [Cook 2015, Xiao 2014]. Beyond its immunological role, RORγ is involved in regulating circadian rhythms and metabolic homeostasis [Jetten 2009]. However, drug development has faced challenges, including concerns over thymic safety and the potential for systemic immunosuppression [Cook 2015, Guntermann 2017].

Other names

RORCNR1F3RORGTORRetinoid-related orphan receptor-gamma

Inverse agonism of the ligand-binding domain to inhibit co-activator recruitment and suppress transcription of pro-inflammatory cytokines [Cook 2015, Xiao 2014]