Synergistic anticancer activity of frankincense aqueous extract with sorafenib in HepG2 cells and its UHPLC–QTOF–MS/MS-based metabolomic profiling

Abstract Liver cancer remains a major global health challenge, with limited therapeutic options for advanced stages. Sorafenib, the standard first-line systemic therapy, provides only modest survival benefits and is frequently associated with drug resistance and adverse effects, necessitating the exploration of safer and more effective combination therapies. Frankincense, the olibanum gum resin from Boswellia sacra Flück.(Burseraceae), has long been used as a traditional medicinal remedy and is known to target multiple biological pathways, with diverse therapeutic activities. Owing to its reported multi-target anticancer, anti-inflammatory, and pro-apoptotic properties, frankincense represents a promising candidate for combination therapy aimed at enhancing sorafenib efficacy while potentially reducing required doses and associated toxicity. This study aimed to evaluate the cytotoxic activity of frankincense aqueous extract (FrAE) alone and in combination with sorafenib (SOR) against the hepatoblastoma cell line HepG2. Phytochemical analysis tentatively identified five diterpenoids and sixteen triterpenoids in FrAE. Both FrAE and SOR exhibited dose-dependent cytotoxicity, and their combination selectively enhanced cytotoxic effects, reducing the effective concentration of SOR and demonstrating strong synergism (CI = 0.298). Mechanistically, the combination induced integrated anticancer effects characterized by enhanced apoptosis and necrosis, activation of autophagic signaling, and marked inhibition of HepG2 cell migration, accompanied by cell cycle disruption across multiple phases. Molecular docking further supported these findings by demonstrating favorable binding of FrAE-derived terpenoids to key apoptotic (BCL-2, p53) and autophagic (mTOR, LC3C) regulators. Collectively, these findings suggest that the aqueous extract of frankincense enhances the anticancer efficacy of sorafenib, representing a promising adjuvant strategy for the management of liver cancer.