Lactucopicrin: A Sesquiterpene Lactone with Anti-Inflammatory Activity Modulates the Crosstalk between NF-kB and AHR Pathways

Chronic inflammatory diseases, including inflammatory bowel diseases and cardiovascular diseases, share inflammation as a central pathological feature. The transcription factors NF-kB and AHR are key regulators of inflammatory responses, yet their interplay remains underexplored in the context of natural anti-inflammatory compounds. This study investigates the anti-inflammatory properties of sesquiterpene lactones derived from <i>Cichorium intybus</i>L. (chicory), focusing on their modulation of NF-kB and AHR signaling pathways. Using a TNFα-induced inflammation model in macrophages, endothelial, and intestinal epithelial cells, we identified lactucopicrin as a potent NF-kB antagonist. Notably, <i>in silico</i> docking and functional assays revealed lactucopicrin as a novel AHR modulator. Crucially, silencing AHR expression attenuated lactucopicrin-mediated NF-kB inhibition, uncovering a previously unrecognized AHR-NF-kB crosstalk mechanism. These findings not only position lactucopicrin as a dual-pathway modulator but also highlight the therapeutic potential of chicory-derived sesquiterpene lactones in treating inflammation-driven diseases, opening new avenues for leveraging natural products in targeted anti-inflammatory strategies.