Insights into Bioactive Constituents from Pericarp of Garcinia mangostana: Anti-Inflammatory Effects via NF-κB/MAPK Modulation and M1/M2 Macrophage Polarization

Mangosteen (<i>Garcinia mangostana</i> L.) has long been used in traditional Southeast Asian medicine to treat inflammatory-related conditions. In this study, three new compounds, including garcimangone A (<b>1</b>), garcimangone B (<b>2</b>), and the <i>S</i>-form of garcimangone C (<b>3</b>), and 18 known compounds were isolated and investigated for their anti-inflammatory properties and effects on M1- and M2-associated markers. Among the isolated components, γ-mangostin (<b>5</b>), garcinone D (<b>6</b>), morusignin J (<b>15</b>), and fuscaxanthone C (<b>16</b>) showed the most potent NO-inhibitory effects in LPS-stimulated RAW264.7 cells. SAR study revealed that chromeno moiety at C-3,4, oxygen substituents at C-1,3,6,7, and isoprenyl groups at C-2,8 are key structural features that promoted anti-inflammatory activity. Cytokine analysis results indicated that morusignin J (<b>15</b>) and fuscaxanthone C (<b>16</b>) could modulate the production of pro-inflammatory cytokines, such as TNF-α and IL-6, while modulating the anti-inflammatory cytokine IL-10. Western blot results demonstrated that morusignin J (<b>15</b>) modulated the inflammatory response through NF-κB and MAPK signaling and increased the expression of M2-associated markers KLF4 and arginase-1 in LPS-induced RAW264.7 macrophages. Further molecular docking analysis confirmed the high binding affinity of morusignin J (<b>15</b>) with key iNOS residues, such as Gln257, Pro344, Glu371, and Hem901, and the in silico prediction supported its potent oral bioavailability and drug-likeness. These in vitro and in silico findings highlight that pericarps of <i>G. mangostana</i> possess potential as promising natural sources for functional extracts and bioactive constituents for the development of antioxidative and anti-inflammatory candidates, and warrant further in vivo investigation in the future.