Primulagenin A is a potent inverse agonist of the nuclear receptor RAR-related orphan receptor gamma (RORγ)
Throughout history, herbal medicines and natural products have played a crucial role as therapeutics for humans, yet their molecular mechanisms of action often remain elusive. Here, we investigate whether primulagenin A (PGA) from the traditionally used herbal substance Primula root acts via the nuclear receptor ROR γ , a key regulator of pro-inflammatory Th17 cells, which are linked to autoimmune diseases like psoriasis. Full-length luciferase assays revealed a high potency (IC 50 = 119 nmol/L) and efficacy ( I max = 87%) of PGA as an inverse agonist of ROR γ . To ensure sufficient supply, we established methods to isolate and synthesize PGA. Its binding to the human ROR γ ligand binding domain was confirmed by nano differential scanning fluorimetry, and a structure–activity relationship was proposed by docking and site-directed mutagenesis. qPCR revealed PGA-mediated downregulation of ROR γ target gene expression. Furthermore, PGA inhibited murine and human Th17 differentiation in a concentration-dependent manner and reduced the proportion of IL-17A-producing Th17 cells, as assessed by flow cytometry. In this work, we identify PGA as a new, potent, and efficacious inverse agonist of ROR γ , with potential for modulating immune responses in inflammatory and autoimmune diseases. The natural product PGA, isolated from Primula sp. and chemically synthesized, is a highly potent inverse agonist of the nuclear receptor ROR γ that effectively inhibits proinflammatory Th17 cell differentiation.
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