Abstract

Oroxylin A (OA), a natural flavonoid, has demonstrated anticancer potential; nevertheless, its precise molecular targets and mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unclear. To address this gap, we integrated network pharmacology, transcriptomic analysis (GSE101448), and molecular docking, which identified SRC as a core therapeutic target of OA. OA exhibited a strong binding affinity to SRC (−9.0 kcal/mol), and molecular dynamics simulation confirmed stable complex formation (RMSD 0.26 ± 0.02 nm). Combined with functional assays, these findings identify SRC as a critical therapeutic target. Importantly, clinical analysis revealed that SRC was significantly upregulated in PDAC tissues, correlating with poor prognosis. Subsequently, in vitro experiments demonstrated that OA dose-dependently suppressed proliferation, induced G2/M cell cycle arrest and apoptosis, and inhibited migration and invasion in MIA PaCa-2 and PANC-1 cells. These effects were accompanied by downregulation of MMP2 and MMP9. Mechanistically, OA selectively inhibited phosphorylation of SRC (Tyr416), PI3K, and AKT (Ser473) without altering total protein levels, suggesting that the SRC/PI3K/AKT axis is a primary pathway mediating OA’s anticancer activity. Furthermore, in vivo treatment with OA significantly reduced tumor growth in a murine xenograft model without observable toxicity, as indicated by stable body weight, normal organ histology, and unaltered serum liver and kidney function markers. Immunohistochemical analysis further confirmed decreased Ki67 and p-SRC/p-AKT expression, alongside increased cleaved caspase-3, in OA-treated tumors. Collectively, these findings identify SRC as a direct target of OA and demonstrate that OA suppresses PDAC progression through the inhibition of the SRC/PI3K/AKT signaling pathway, thereby supporting its potential as a safe and effective therapeutic candidate for pancreatic cancer.

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