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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
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DOI：10.1016/j.lddd.2025.100253.png)
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Abstract
En 中文
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.
Keywords:
Oral squamous cell carcinoma
Squamocin
Peroxisome proliferator activated receptorgamma
Molecular docking
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