Characterisation of the honokiol derivative LRK071 as a dual-specific RXR agonist and PDE4 inhibitor

Retinoid X Receptor (RXR), a ligand-activated transcription factor, and Phosphodiesterase 4 (PDE4), an enzyme that degrades cyclic AMP (cAMP), regulate key physiological processes, including immune response, inflammation, and cell differentiation [ 1 ] [ 2 ]. Consequently, RXR agonists and PDE4 inhibitors have been explored for various therapeutic applications. Despite their distinct mechanisms, their converging effects suggest potential synergy, which could be leveraged for treatments such as promoting remyelination in neurodegenerative conditions [ 3 ] [ 4 ]. In this study, the honokiol derivative LRK071 was identified as an RXR agonist following a screening of 55 neolignans using nuclear receptor luciferase assays. LRK071 exhibited increased specificity for RXR over other nuclear receptors compared to its parent compound, honokiol. Its RXR agonism was further validated in THP1 macrophages by the upregulation of RXR homodimer and RXR:LXRα heterodimer-driven target gene expression using RT-qPCR. In addition, LRK071 showed potential as a PDE4 inhibitor by increasing cAMP levels in a concentration-dependent manner in an EPAC-based FRET biosensor assay [ 5 ]. No such effect was seen for the marketed RXR agonist, Bexarotene, indicating the effect was RXR-independent. Further characterization using a CRE-Luciferase assay confirmed the ability of LRK071 to induce the anti-inflammatory cAMP-PKA-CREB pathway, comparable to known PDE4 inhibitors.In conclusion, our data suggest that LRK071 is a dual-specific RXR agonist and PDE4 inhibitor with potential for synergistic therapeutic applications. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany