Head and neck squamous cell carcinoma (HNSCC) involves complex dysregulation of metabolic, inflammatory, and proliferative pathways, limiting the effectiveness of single target therapies. Medicinal plants containing multiple bioactive compounds may provide complementary strategies to modulate cancer related networks. Hemidesmus indicus ( H. indicus ) has been reported to have anticancer activity, but its relevance to HNSCC remains insufficiently defined.

HNSCC–related targets of H. indicus phytochemicals were identified using an integrated network pharmacology approach. Drug-likeness, pharmacokinetics, and toxicity were assessed, followed by protein–protein interaction analysis, functional enrichment, gene expression, survival, and druggability evaluation. Molecular docking was performed against prioritized hub targets. Experimental validation was performed in KB cells using an MTT cytotoxicity assay, acridine orange/ethidium bromide staining, Rhodamine 123 mitochondrial membrane potential analysis, and quantitative real-time PCR.

Eighty-five overlapping targets between H. indicus phytochemicals and HNSCC genes were identified, with PPARG, PTGS2, PPARA, HMGCR, and MAPK3 emerging as hub genes. Enrichment analyses highlighted roles in metabolic regulation, inflammatory signaling, and cancer-associated pathways. Docking studies demonstrated moderate to favorable binding of selected phytochemicals to PPARA and PTGS2. In vitro assays showed concentration-dependent cytotoxicity, apoptotic morphological changes, and mitochondrial membrane depolarization in KB cells. qPCR revealed increased PPARA expression and reduced PTGS2 expression.

These findings provide preliminary support for the potential relevance of H. indicus in HNSCC research and emphasize the need for further in vivo and mechanistic investigations.