María Ángeles Ávila‐Gálvez, Catarina J G Pinto, Carlos Rafael-Pita, Inês P. Silva, Aleksandra T. Janowska, Sérgio Marinho, Rory Saitch, Yilong Lian, Pakavarin Louphrasitthiphol, Jonas Protze, Gerd Krause, Pedro Moura‐Alves, Cláudia Nunes dos Santos
Abstract 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 Cichorium intybusL. (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, in silico 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.