Ergosterol, a Novel RORγt Inverse Agonist, Enhances Skin Barrier Function and Reduces Skin Inflammation in...

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is one of the nuclear receptor transcription factors that plays a key role in the differentiation of pro-inflammatory IL-17⁺ T helper cells. Recently, RORγt has attracted increasing attention as a potential drug target for the treatment of several human inflammatory diseases, including psoriasis and Crohn's disease. In this study, we revealed that ergosterol (ERG) was a novel RORγt inverse agonist, which decreased RORγt transcriptional activity, to regulate collagen fiber deposition and to inhibit pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17, IL-22, and IL-23 in the skin lesions of IMQ-induced mice with psoriasis. Furthermore, ERG could repair the epidermal barrier function by upregulating tight junction proteins, such as claudin, occludin, and ZO-1, thereby alleviating psoriasis symptoms. These findings suggested that ERG might be used as a promising novel RORγt inverse agonist in the management of psoriasis.