Bakuchiol: Meroterpenoid Obtained from Psoralea glandulosa L., Positively Impacts on Nrf2-Stability and Activity of Nrf2/HO-1 Signaling Pathway

Psoralea glandulosa L. is a native Chilean plant, traditionally used as an antipyretic, antibacterial, and wound-healing remedy. It exhibits antioxidant, anti-inflammatory, antimicrobial, antitumor, and antipyretic bioactivities, attributed to its high terpenoid and flavonoid contents. Our previous investigations showed that its extracts and resin exert antioxidant activity, with high meroterpenoid Bakuchiol (BAK) content in stems, roots, leaves, and flowers. However, the underlying molecular mechanisms remain unclear. This study aimed to evaluate whether the resinous exudate, dichloromethane (DCM) extract of P. glandulosa L., and BAK activate the Nrf2/HO-1 signaling axis in human keratinocytes. Dose–response assays were conducted in human epidermal keratinocytes (HaCaT). We assessed Nrf2/HO-1 total protein levels, Nrf2 nuclear enrichment, ubiquitination, and CHX-chase by immunoblotting. We evaluated Nrf2 and downstream gene expression and transcriptional activity using RT-qPCR and Dual-Luciferase Reporter assays, respectively. Molecular docking was performed to gain insight into BAK interactions with pathway players. Resinous exudate, DCM extract, and BAK increased total Nrf2 levels. Moreover, BAK promoted Nrf2 nuclear translocation and stabilization, extending its half-life, in correlation with increased ubiquitination. Both DCM extract and BAK upregulated Nrf2 and downstream genes, strongly inducing HO-1 expression, supported by enhanced Nrf2 ARE-mediated transcriptional activity. Docking analysis predicted that BAK interacts with Keap1 at the Kelch domain, contributing to Nrf2 stabilization. These findings support the antioxidant activity of BAK through activation of the Nrf2/HO-1 signaling axis and identify BAK as a promising candidate for further investigation as a potential therapeutic agent for oxidative stress-related disorders.