Triterpenes from Chios mastic gum as dual RORγ and TGR5 modulators

The retinoic acid receptor-related orphan receptor γ (RORγ) and the G-protein-coupled bile acid receptor (TGR5) regulate Th17 cell differentiation and metabolic and immune functions, respectively [ 1 ] [ 2 ]. Their dual modulation may provide a novel therapeutic approach for inflammatory diseases [ 3 ]. Chios Mastic Gum (CMG), the exudate of Pistacia lentiscus var. Chia (Anacardiaceae), is rich in triterpenes like masticadienoic (MNA) and isomasticadienoic (IMNA) acid [ 4 ] [ 5 ]. Given their structural similarity to known RORγ and TGR5 ligands, we hypothesized that these compounds may act as modulators of these receptors. An extract containing a mixture of MNA and IMNA, along with the purified compounds, were tested. TGR5 activity was assessed using a CRE-Luciferase reporter gene assay in TGR5 HEK EPAC cells, which express an EPAC (exchange protein directly activated by cAMP)-based FRET biosensor. RORγ activity was evaluated with a RORγ-Gal4 luciferase reporter assay in HEK293 cells. The extract and MNA were active on both receptors. Both 24E-IMNA and 24Z-IMNA activated TGR5, but only the Z configuration was active on RORγ. Potencies, determined by nonlinear regression, ranged from nanomolar to low micromolar concentrations. Additionally, luciferase assays confirmed that these compounds showed no activity on other nuclear receptors, including LXRα, FXR, and VDR. Cytotoxicity was assessed via a resazurin conversion assay, indicating no toxicity in HEK293 cells at 1-10 μM concentrations. These preliminary results suggest that these compounds may modulate RORγ and TGR5, warranting further investigation. Future studies will include NF-κB assay and RT-qPCR in functional cell models to further explore their therapeutic potential. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany