System Pharmacology Profiling of Plumbago zeylanica Linn. Against HPV-Associated Cervical Cancer

Vollständiger Abstract

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Background: Cervical cancer remains a significant contributor to cancer-related deaths in women globally, with persistent infection by high-risk Human Papillomavirus (HPV) identified as its principal etiological driver. Aim: This study explored the mechanistic basis of Plumbago zeylanica’s potential anti-cervical cancer activity through a combined network pharmacology and molecular docking framework targeting HPV-associated pathogenic processes. Methods: Bioactive phytoconstituents of P. zeylanica were systematically compiled from published literature and the IMPPAT 2.0 database, then filtered through ADME criteria to retain compounds meeting drug-likeness thresholds. Putative protein targets for the shortlisted compounds were obtained via SwissTargetPrediction and SEA platforms, while genes linked to HPV-driven cervical carcinogenesis were sourced from the GeneCards repository using curated disease- and pathogen-specific search terms. Overlapping targets were mapped and used to construct a Protein–Protein Interaction (PPI) network, from which hub genes were identified through topological parameter analysis. Gene Ontology and pathway enrichment analyses were subsequently applied to delineate relevant biological processes, with emphasis on viral oncogenesis and immune-inflammatory signalling. Binding interactions between key phytoconstituents and prioritised hub proteins were then evaluated through molecular docking simulations. Results: Topological analysis of the PPI network highlighted JUN, NFKB1, IL1B, EGFR, and TNF as critical regulatory nodes within HPV-mediated oncogenic and inflammatory cascades. Pathway enrichment pointed to significant involvement of cancer-related pathways, TNF signalling, programmed cell death, immune checkpoint modulation, and viral infection mechanisms. Among the docked compounds, zeylanone emerged as the most promising candidate, displaying robust binding affinity toward JUN (−10.2 kcal/mol) and EGFR (−9.0 kcal/mol), while plumbagin, formononetin, diosmetin, and hispidulin also demonstrated favourable docking profiles against multiple targets. Conclusion: Collectively, these results indicate that Plumbago zeylanica may interfere with cervical cancer progression by simultaneously modulating several HPV-associated oncogenic signalling nodes. Nonetheless, rigorous in vitro and in vivo experimental validation remains essential to substantiate its clinical translational value. Major Findings: Network pharmacology study of Plumbago zeylanica identified JUN, NFKB1, IL1B, EGFR, and TNF as key targets involved in HPV-associated cervical cancer. Among the phytoconstituents, zeylanone exhibited the strongest multitarget binding affinity, followed by formononetin, diosmetin, hispidulin, and plumbagin. All had considerable multi-target interactions, which suggest a coordinated multi-component mechanism of action.