Phytochemical Profiling, Molecular Docking, and ER Stress‐Mediated Apoptosis Induced by Plantago loeflingii L. Essential Oil in Ovarian Adenocarcinoma Cells

ABSTRACT

Plantago loeflingii L. (Plantaginaceae) is traditionally used for wound healing and tumor treatment, yet its cellular effects remain unexplored. This study provides the first integrated evaluation of its essential oil (PLA‐EO), including chemical composition, cytotoxicity, mechanistic assays, and molecular docking. Hydrodistillation followed by GC–MS/GC–FID identified 53 constituents (98.33%), dominated by linalool (23.81%), palmitic acid (15.34%), limonene (10.54%), thymol (8.51%), and α‐terpineol (5.23%). PLA‐EO selectively inhibited ovarian adenocarcinoma BG‐1 cells (IC ₅₀  = 5.67 ± 0.6 µg/mL) while sparing MCF7, A549, and normal cells. Mechanistic assays revealed ER stress‐mediated apoptosis, as indicated by ER expansion, GRP78 upregulation, Ca ^{2 +} overload, and caspase‐3 activation. To explore upstream triggers, molecular docking was performed against the EGFR kinase domain (PDB: 3W2S). The docking protocol was validated by redocking (RMSD = 0.98 Å), and erlotinib (−8.96 kcal/mol) reproduced known interactions with ASP855, ALA859, and PHE723. Palmitic acid (−9.05 kcal/mol) interacted with ARG836 via hydrogen bonding and hydrophobic contacts, while linalool (−7.17 kcal/mol) engaged ASP855 and PHE723. These interactions suggest possible EGFR modulation, though activity likely reflects synergistic contributions from multiple PLA‐EO components. In conclusion, PLA‐EO exhibits selective cytotoxicity in ovarian cancer cells via ER stress pathways, supported by in silico evidence of EGFR targeting. The combined phytochemical, cellular, and docking results highlight P. loeflingii as a promising source of bioactive essential oils, warranting further in vivo validation.