First report of chalcones in Corema album berries: Multi-target suppression of macrophage inflammation through COX-2 inhibition and NF-κB modulation.

Corema album, an Atlantic endemic berry traditionally consumed in the Iberian Peninsula, is gaining increasing attention due to its rich phenolic profile. Here, we report for the first time the isolation, structural characterization, and quantification of three chalcones from their fruits: 2',4'-dihydroxydihydrochalcone, 2',4'-dihydroxychalcone, and 2'-methoxy-4'-hydroxydihydrochalcone. Structural elucidation was achieved by NMR and mass spectrometry, and quantification was performed by UHPLC-HRMS. Their antioxidant and anti-inflammatory activities were evaluated in human (THP-1) and murine (RAW 264.7) macrophage models. All compounds significantly reduced intracellular ROS levels under oxidative stress conditions and suppressed LPS-induced production of IL-6 and TNF-α. In RAW 264.7 cells, 2',4'-dihydroxychalcone and 2'-methoxy-4'-hydroxydihydrochalcone decreased nitric oxide production through iNOS downregulation. Moreover, chalcones inhibited COX-2 activity in vitro (IC₅₀ ≈ 45 µM) and modulated NF-κB-related signaling markers, including NF-κB p65, IκBα and IL-1β expression. Notably, 2',4'-dihydroxychalcone increased HO-1 protein levels in both macrophage models. These results highlight the multi-target anti-inflammatory potential of C. album chalcones, mediated through coordinated regulation of oxidative stress and key inflammatory pathways. The findings provide mechanistic support for the traditional use of these berries and underscore their promise as natural anti-inflammatory agents. Further in vivo studies are warranted to evaluate their therapeutic efficacy.