Network-Guided Identification of Plant-Derived Modulators of Stress-Adaptive Signalling in Neuroblastoma

Neuroblastoma is characterized by noticeable resistance to chemotherapy, largely driven by the ability of tumour cells to reorganize stress-adaptive signalling networks rather than relying on single oncogenic drivers. We conducted a study to investigate the pharmacological mode of action of doxorubicin in modifying adaptive signalling pathways in SH-SY5Y neuroblastoma cells, and whether the capacity of plant metabolites can exploit emergent biochemical vulnerabilities. Transcriptomic profiling through RNA sequencing conducted 48 h post-doxorubicin exposure unveiled the organized disruption of pathways linked with amyloidogenic processes, oncogenic signalling pathways, oxidative stress, and DNA repair. The protein-protein interactions, coupled with Kyoto Encyclopedia of Genes and Genomes pathway evaluations, revealed five network-central-hubs: BRAF, GSK3β, PARP1, BACE1, and MAOB. Structural docking integrated with 200 ns molecular dynamics simulations illustrated binding stability across multiple targets driven by three metabolites, Lactol binding to BRAF (-54.13 kcal/mol) and MAOB (-39.08 kcal/mol), Amino(1H-indol-2-yl)acetic acid to BACE1 (-41.07 kcal/mol) and GSK3β (-47.38 kcal/mol), and Quercetin-3-(6″-malonyl-glucoside) binding to PARP1 (-46.03 kcal/mol). In vitro Cell Counting Kit-8 proliferation assays validated the significant anti-neuroblastoma efficacy, with the lowest IC₅₀ (0.2397 µM) being exhibited by Amino(1H-indol-2-yl)acetic acid, followed by Lactol (1.226 µM) and Quercetin-3-(6″-malonyl-glucoside) (1.301 µM), which mirrored the cytotoxic action of doxorubicin (1.306 µM). These results suggest that plant-derived metabolites may interact with stress-adaptive signalling pathways connected with neuroblastoma. However, direct experimental validation of target engagement and pathway modulation will be required to confirm these predicted interactions.