Background and Aim. Pancreatic ductal adenocarcinoma (PDAC) exhibits nearuniversalFOLFIRINOX chemoresistance driven by constitutive NF-κB activation,mTOR-mediated autophagy suppression, and P-glycoprotein drug efflux. Thisstudy computationally evaluates whether phytochemicals from Spirulina platensis(Arthrospira platensis Gomont, Oscillatoriaceae) and Moringa oleifera Lam.(Moringaceae) represent candidate chemosensitisation agents for KRASG12D-mutantPDAC, generating specific testable hypotheses for subsequent experimental validation.Methods. An eight-layer computational pipeline was deployed: ADMET/Lipinski/QED filtering, compound–target–disease network pharmacology, PPIhub gene identification, AutoDock-GPU v1.6 molecular docking (Lamarckian GeneticAlgorithm), 100 ns molecular dynamics simulation with MM-PBSA, Bliss/Loewe/ZIPsynergy modelling, Boolean/ODE pathway simulation with rule-perturbation sensitivityanalysis, and TCGA-PAAD transcriptomic target validation with GATA6subtype stratification.Results. Nine drug-like compounds target 30 PDAC disease genes (96.8% overlap;Monte Carlo randomisation p < 10−4, 184-fold enrichment). NF-κB1 emerged asthe dominant hub (degree = 10). AutoDock-GPU validated β-sitosterol binding toEGFR (ΔG = −7.98 kcal/mol) and NF-κB p65/RELA (−7.70 kcal/mol). The triplecombination achieved 87.9% predicted cell death versus 83.3% for FOLFIRINOXalone (Boolean model robust under 66.4% of permuted rule sets). Hub targets arespecifically hyper-activated in FOLFIRINOX-resistant basal-like PDAC (enrichmentp = 2.94×10−74). Bioavailability-adjusted scoring identifies niazimicin (Foral = 45%)as the most pharmacologically realistic lead.Conclusions. Computational evidence supports a “three-pronged siege” hypothesisin which Spirulina and Moringa phytochemicals may modulate PDAC resistancepathways. A 48–72 h Moringa washout protocol is proposed to mitigate the identifiedCYP3A4–irinotecan herb–drug interaction. These predictions warrant experimentalvalidation in PANC-1 models before any clinical extrapolation.Keywords: pancreatic cancer · network pharmacology · molecular docking · Spirulinaplatensis · Moringa oleifera · FOLFIRINOX