Guggulsterone-Mediated Selective Modulation of Nuclear Receptors: Implications for FXR-PXR Signaling and Hepatic Metabolic Homeostasis.

Guggulsterone (GSS), a plant-derived steroid from Commiphora mukul, exhibits complex pharmacological behavior through modulation of nuclear receptors and detoxification enzymes. Acting as an antagonist of the Farnesoid X receptor (FXR) and an agonist of the Pregnane X receptor (PXR), guggulsterone influences the transcription of cytochrome P450 enzymes (notably CYP3A4 and CYP2C9) and transporters such as MDR1 and OAT2. This review synthesizes current mechanistic insights from molecular, pharmacokinetic, and in silico analyses, highlighting its dual regulatory effects on metabolism and drug resistance. Despite therapeutic promise in metabolic disorders, poor bioavailability and bile acid dysregulation pose translational challenges. Future work should emphasize isomer-specific activity, delivery optimization, and human-relevant models to clarify its pharmacological and toxicological potential.