Integrative Transcriptomics and Phytochemical Screening Reveal Pratenol B, Eriodictyol, Losbanine, and Isookanin, as Potential EGFR and HRAS Inhibitors in Indian Oral Squamous Cell Carcinoma Patients

Abstract Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer, with India contributing nearly one-third of the global cases. Management of OSCC remains difficult due to increasing risk factors, limited therapeutic options, severe side effects, and rising drug resistance. Therefore, novel and safer treatment strategies are urgently needed. This study explores the potential of phytochemicals as targeted inhibitors of key dysregulated biomarkers in Indian OSCC patients. RNA sequencing and pathway analysis revealed significant alterations in the MAPK signaling pathway, highlighting EGFR and HRAS as crucial therapeutic targets. Given the limited clinical success of existing EGFR-targeted therapies and the scarcity of HRAS inhibitors, a natural product-based approach was adopted. Molecular docking of 17,000 phytochemicals identified Pratenol B, Eriodictyol, Losbanine, and Isookanin as promising inhibitors, with Pratenol B showing dual inhibition of EGFR and HRAS. These compounds exhibited strong binding affinities, favorable pharmacokinetic profiles, high bioavailability, and low toxicity. Molecular dynamics simulations confirmed the stability of Pratenol B with both target proteins, surpassing reference inhibitors. Utilizing vast medicinal plant diversity presents a cost-effective and low-toxicity avenue for OSCC therapy. Further in vitro, in vivo, and clinical studies are warranted to validate these phytochemicals as potential therapeutics. Competing Interest Statement The authors have declared no competing interest. Abbreviations - ADMET - Absorption, Distribution, Metabolism, Excretion, and Toxicity - AMPK - AMP-Activated Protein Kinase - AREG - Amphiregulin - BBB - Blood-Brain Barrier - CDC25B - Cell Division Cycle 25B - c-Myc - Cellular Myelocytomatosis Oncogene - CNS - Central Nervous System - DEGs - Differentially Expressed Gene - DMSO - Dimethyl Sulfoxide - EGFR - Epidermal Growth Factor Receptor - FDA - Food and Drug Administration - GO - Gene Ontology - GCO - Global Cancer Observatory - HRAS - Harvey Rat Sarcoma Viral Oncogene Homolog - HSPA8 - Heat Shock Protein Family A (Hsp70) Member 8 - hERG I/II - Human Ether-à-go-go-Related Gene Potassium Channel Inhibitors (hERG I and II) - IMPPAT - Indian Medicinal Plants, Phytochemistry, and Therapeutics - IL1A - Interleukin 1 Alpha - KRAS - Kirsten Rat Sarcoma Viral Oncogene Homolog - KEGG - Kyoto Encyclopedia of Genes and Genomes - MET - MET Proto-Oncogene, Receptor Tyrosine Kinase - MAPK - Mitogen-Activated Protein Kinase - NRAS - Neuroblastoma Rat Sarcoma Viral Oncogene Homolog - NF-κB - Nuclear Factor Kappa B - OSCC - Oral squamous cell carcinoma - PRAD-1 (also known as Cyclin D1) - Parathyroid Adenoma 1 - P-gp - P-Glycoprotein - pkCSM - pharmacokinetics-chemical space modeling - PI3K - Phosphoinositide 3-Kinase - PDB - Protein Data Bank - RMSD - Root Mean Square Deviation - RMSF - Root Mean Square Fluctuation - TGFA - Transforming Growth Factor Alpha - VEGFC - Vascular Endothelial Growth Factor C