SYSTEMS PHARMACOLOGY AND MOLECULAR DOCKING UNCOVER THE MULTI-TARGET ANTICANCER LANDSCAPE OF SPHAGNETICOLA CALENDULACEA AGAINST OSTEOSARCOMA OF THE URINARY BLADDER

Abstract

Osteosarcoma of the urinary bladder is an exceptionally rare mesenchymal malignancy for which no standardised pharmacological regimen exists, and current management is largely extrapolated from urothelial carcinoma protocols. Sphagneticola calendulacea (L.) Pruski, an Asteraceae herb used across South and Southeast Asian traditional medicine for genitourinary and inflammatory disorders, contains a broad phytochemical repertoire whose molecular targets in this malignancy remain uncharacterised. Here we applied an integrated network pharmacology and molecular docking pipeline to identify the multi-target mechanism by which S. calendulacea phytoconstituents may act against bladder osteosarcoma. Twenty-six phytochemicals were mapped to 202 non-redundant human protein targets, which were intersected with 521 disease-associated genes retrieved from GeneCards, yielding 45 shared targets. Protein–protein interaction network analysis in STRING (78 nodes, 510 edges, enrichment p < 1.0 × 10⁻¹⁶) combined with CytoHubba topological ranking identified STAT3, HSP90AA1, HIF1A, MDM2, ESR1, AKT1, NFKB1, CCND1, SRC and ERBB2 as hub genes, with STAT3 attaining the highest maximal clique centrality score. Gene Ontology and KEGG enrichment linked the shared targets to nitric-oxide synthase regulation, estrogen-response element binding, and the bladder cancer, prolactin, and EGFR-tyrosine-kinase-inhibitor-resistance pathways. Molecular docking of stigmasteryl glucoside into the STAT3 crystal structure (PDB: 6NUQ) revealed a binding energy of −9.47 kcal/mol, stabilised by hydrogen bonds with Gly127 and Ser388 (2.11 Å and 2.27 Å) and hydrophobic contacts with Ala124, Cys125, Pro130, Ile132, Arg199 and Pro210. These findings nominate STAT3 as the principal druggable node underlying the anti-osteosarcoma potential of S. calendulacea and provide a mechanistic, structurally resolved rationale for downstream molecular dynamics and experimental validation of stigmasteryl glucoside as a lead phytotherapeutic.