Beauvericin exhibits antitumor activity in pancreatic cancer cells: Integrative analysis suggests potential modulation of the KEAP1-NRF2-HMOX1 axis and survival signaling pathways

Abstract

To investigate the anticancer effects of Beauvericin (BEA) and elucidate its potential mechanisms in pancreatic cancer cells, a malignancy characterized by marked heterogeneity and frequent chemoresistance. The effects of BEA on the proliferation, migration and apoptosis of Mia PaCa-2 cells were evaluated via CCK-8, colony formation, Transwell and flow cytometry assays. Systems biology was used to prioritize candidate targets, and molecular docking and molecular dynamics simulations were performed to evaluate a putative BEA–KEAP1 interaction computationally. Western blotting was used to detect the expression of key signaling pathway proteins. In Mia PaCa‑2 cells, BEA reduced cell viability (IC₅₀ = 1.45 µM), suppressed colony formation at 0.5 µM, decreased migration at 1 µM, and increased apoptosis to 50.06% at 2 µM. Docking suggested the presence of putative interactions between BEA and KEAP1 (estimated docking score/energy of -9.45 kcal/mol) and between BEA and HMOX1 (-7.82 kcal/mol). MD simulations supported the stability of the predicted BEA–KEAP1 complex (RMSD ~ 0.5 nm). BEA treatment was associated with the modulation of KEAP1/NRF2‑related signaling and reduced the phosphorylation of AKT, ERK1/2, and STAT3, which is consistent with the attenuation of key survival signaling. Proteomic profiling revealed enrichment of differentially expressed proteins involved in oxidative phosphorylation and ribosome‑related processes following BEA treatment. BEA had dose-dependent effects on Mia PaCa-2 cells and affected multiple signaling nodes. These findings support further investigations of BEA in additional PAAD models, including chemoresistant settings, to evaluate its translational potential.