Exploring the mechanism of Squamocin inhibits oral squamous cell carcinoma malignant progression by targeting peroxisome proliferator activated receptor-gamma based on network pharmacology and molecular docking

Background Oral squamous cell carcinoma (OSCC) is a highly metastatic malignant tumor that originates from the squamous epithelium of oral mucosa. Squamocin, a compound derived from traditional Chinese medicine, has been shown to inhibit head and neck squamous cell carcinoma, yet its mechanism in OSCC remains unclear. Methods Cell functions were assessed using the 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT), 5-ethynyl-2’-deoxyuridine (EdU), flow cytometry, transwell, wound healing, and sphere-formation assays. Potential targets of Squamocin in OSCC were predicted via the SwissTargetPrediction and GeneCards databases. A protein-protein interaction (PPI) network was constructed with STRING and visualized in Cytoscape. Gene and protein expression levels were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. Molecular docking and cell thermal shift assay (CETSA) were used to examine the binding between Squamocin and peroxisome proliferator activated receptor-gamma (PPARG). Results Squamocin treatment inhibited OSCC cell viability ( P  < 0.05), proliferation ( P  < 0.01), migration ( P  < 0.01), and sphere formation ( P  < 0.01), while promoting apoptosis ( P  < 0.01). PPARG was identified as the key target of Squamocin and was down-regulated in OSCC cells ( P  < 0.05). Notably, PPARG expression was increased by Squamocin ( P  < 0.01), and the stable binding between them was confirmed by molecular docking (-6.6 kcal/mol) and CETSA ( P  < 0.01). Functional assays revealed that PPARG overexpression suppressed OSCC malignancy ( P  < 0.05), while its knockdown attenuated the inhibitory effects of Squamocin ( P  < 0.01). Conclusion Squamocin inhibits the malignant phenotypes of OSCC by activating PPARG. These findings provide the first evidence that PPARG is a direct functional target of Squamocin in OSCC, suggesting its potential as a novel therapeutic agent for OSCC. Furthermore, given the central role of PPARG in OSCC progression, these findings highlight its potential as a target for novel small RNA-based therapeutics, such as microRNA (miRNA) mimics or antisense oligonucleotides, offering a promising direction for future precision medicine approaches in oral cancer.