Network pharmacology-guided elucidation and validation of Schisandrin B’s antitumor effects via EGFR/AKT/mTOR signaling in pancreatic cancer

Background and Purpose Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and limited response to standard therapies like gemcitabine, largely due to drug resistance and tumor microenvironmental barriers. This study aimed to investigate the anticancer potential of Schisandrin B (Sch B), a natural compound derived from Schisandra chinensis, and elucidate its mechanisms of action in PDAC through a network pharmacology-guided approach. Experimental Approach Network pharmacology and molecular docking were employed to predict Sch B targets and binding interactions. In vitro studies using PDAC cell lines evaluated proliferation, apoptosis, mitochondrial dysfunction, calcium dysregulation, and ROS production. The synergistic potential of Sch B with gemcitabine was assessed via Chou-Talalay analysis. In vivo efficacy was tested using a PANC-1 xenograft mouse model. EGFR knockdown experiments further clarified Sch B’s mechanism. Key Results Sch B inhibited PDAC cell proliferation and induced mitochondria-dependent apoptosis via disruption of mitochondrial membrane potential, calcium imbalance, and elevated ROS. Key molecular targets included EGFR, AKT, mTOR, BCL-2, and HSP90. EGFR knockdown enhanced Sch B-induced mitochondrial dysfunction and apoptosis. Sch B exhibited synergistic effects with gemcitabine, enhancing cytotoxicity and mitochondrial stress. Sch B significantly suppressed tumor growth and downregulated EGFR/AKT/mTOR signaling in vivo. Conclusions and Implications Sch B exerts potent anticancer effects in PDAC by targeting the EGFR/AKT/mTOR axis and inducing mitochondrial dysfunction. Its ability to synergize with gemcitabine suggests that Sch B may serve as a promising candidate for combination therapy or as an alternative chemotherapeutic agent in PDAC treatment. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 232views 183downloads Citations Download citation Woonghee Lee, Gwonhwa Song, Hyocheol Bae. Network pharmacology-guided elucidation and validation of Schisandrin B’s antitumor effects via EGFR/AKT/mTOR signaling in pancreatic cancer. Authorea. 02 May 2025. DOI: https://doi.org/10.22541/au.174620745.53059729/v1 DOI: https://doi.org/10.22541/au.174620745.53059729/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.