Targeting the PAK1 Signaling Hub in Cancer: A System Pharmacology and In Silico Investigation of Propolis-Derived Prenylated Flavonoids

p21-activated kinase 1 (PAK1) serves as a critical node in oncogenic signaling, integrating pathways such as MAPK and PI3K/Akt to drive cell survival and metastasis. The present study investigates the potential of these propolis-based compounds to act as multi-targeting PAK1 inhibitors and evaluates their impact on global cancer-related signaling pathways using a combined in silico approach. DFT was employed to assess the chemical stability and reactivity of the compounds. System pharmacology, utilizing KEGG Mapper, was conducted to visualize the expansive impact of these bioactives on human signaling. KEGG enrichment analysis identified a significant convergence of all four compounds on Pathways in cancer (147), MAPK signaling (120), and PI3K-Akt signaling (95). Molecular docking results validated the strong inhibitory potential, with Nymphaeol C emerging as the lead candidate, showing a binding affinity of -10.49 kcal/mol and a nanomolar-range inhibition constant toward PAK1. Our findings demonstrate that nymphaeols and artepillin C function as a coordinated chemical unit that targets the PAK1 hub, effectively suppressing large-scale oncogenic networks. This study provides a robust molecular framework for the use of regional propolis bioactives as systemic anticancer agents. System-level metabolic modeling using Human-GEM further confirmed that targeting this 37-gene consensus set reduces A549 growth flux by 12.86% To further validate this interaction under fully flexible, explicit-solvent conditions, a 98.7-ns all-atom molecular dynamics (MD) simulation and MM-GBSA binding free energy calculation were performed on the Nymphaeol C–PAK1 complex, confirming a stable, van der Waals-dominated engagement within the catalytic pocket (ΔG_bind = -43.86 ± 3.60 kcal/mol).