Essential oils from fruits of Zanthoxylum armatum exhibit antioxidant, anti-inflammatory, and anticancer properties by inhibiting p38-MAPK pathway

Essential oils from Zanthoxylum armatum fruits, known for their therapeutic properties, were extracted from three regions of Nepal: Myagdi (EO1), Surkhet (EO2), and Salyan (EO3). GC–MS analysis identified linalool as the predominant compound (58.31 %, 58.45 %, and 80.37 % in EO1, EO2, and EO3, respectively), along with limonene and trans -methyl cinnamate. These oils exhibited strong antioxidant activity as assessed by ferric reducing power, phosphomolybdenum capacity, and NO scavenging along with anti-inflammatory effects by reducing albumin denaturation and NO production in LPS-induced RAW 264.7 cells. Cytotoxicity assays showed dose-dependent effects against lung (NCI-H460), skin (A431), and prostate (PC3) cancer cells, with the highest activity in NCI-H460 (IC 50 = 78.5 μg/mL). Mechanistic studies revealed reduced clonogenicity, inhibited migration, S-phase cell cycle arrest, and apoptosis via downregulation of RACK1, p38 MAPK, c-MYC, Vimentin, and Bcl-2. In silico docking confirmed strong interactions of linalool and limonene with p38 MAPK and c-MYC, respectively. These results highlight the potential of Z. armatum essential oils for antioxidant, anti-inflammatory, and anticancer applications. Mechanism of action of Z. armatum essential oil for its anti-cancer activities. • GC–MS of Z. armatum essential oils identified linalool (major), limonene, and trans -methyl cinnamate as key components. • Essential oils exhibited strong antioxidant effects in ferric reducing power, phosphomolybdenum, NO scavenging assays. • Essential oils effectively inhibited albumin denaturation and reduced NO production in LPS-induced rAW 264.7 macrophages. • EO3 showed the strongest cytotoxicity in NCI-H460 cells, inducing S-phase arrest and apoptosis while inhibiting migration. • EO3 downregulated the p38 MAPK pathway; docking confirmed strong binding of its constituents with p38 and c-MYC.