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<p>Globally, non-small cell lung carcinoma (NSCLC) ​continues to be a major contributor to​ deaths from cancer. Sanguinarine (SNG), a naturally occurring benzophenanthridine alkaloid, has demonstrated considerable anti-cancer properties, yet its precise molecular mechanisms in NSCLC remain inadequately defined. Bioinformatic workflows comprised SNG target screening (TCMSP and SEA), acquisition of NSCLC-associated genes (GeneCards and CTD), PPI network assembly (STRING), ​and key target discovery through topological evaluation​ (Cytoscape). Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analyses ​served to​ analyze target functional/pathway enrichment, while molecular docking validated SNG-core target binding. Experimentally, cell proliferation was assessed using Cell Counting Kit-8 and clonogenic assays. Apoptosis and autophagy were analyzed by flow cytometry, Western blot, and qRT-PCR. Computational pharmacology identified 16 principal molecular targets and emphasized the PI3K-AKT signaling pathway. SNG exhibited dose-responsive suppression of cellular viability and clonogenic capacity, alongside induction of apoptosis through <i>BAX</i> and <i>BCL-2</i> regulation. Mechanistically, SNG triggered cytoprotective autophagy, evidenced by enhanced <i>Beclin-1</i> expression, LC3-I to LC3-II conversion, and reduced p62 levels. Autophagy suppression markedly attenuated SNG’s anti-tumor activity. Moreover, SNG exhibited high binding affinity to key targets (<i>ANXA5</i>, <i>STAT1</i>, and Peroxisome Proliferator-Activated Receptor Gamma (<i>PPARG</i>)). Subsequent <i>PPARG</i> upregulation suppressed this critical oncogenic pathway. SNG exerts anti-neoplastic effects against NSCLC by promoting apoptosis and triggering cytoprotective autophagy, primarily through enhancing <i>PPARG</i> expression to suppress the PI3K-AKT signaling cascade.</p>

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Sanguinarine Antagonizes NSCLC Through PPARG-Mediated PI3K/AKT Suppression and Autophagic Apoptosis

  • 期刊论文

  • 发表日期：

    2025年12月13日

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  • Baoyi Zhang,
  • Zhaidong Liu,
  • Huijie Li,
  • Qinglin Jian,
  • Xin Dai

摘要

Globally, non-small cell lung carcinoma (NSCLC) ​continues to be a major contributor to​ deaths from cancer. Sanguinarine (SNG), a naturally occurring benzophenanthridine alkaloid, has demonstrated considerable anti-cancer properties, yet its precise molecular mechanisms in NSCLC remain inadequately defined. Bioinformatic workflows comprised SNG target screening (TCMSP and SEA), acquisition of NSCLC-associated genes (GeneCards and CTD), PPI network assembly (STRING), ​and key target discovery through topological evaluation​ (Cytoscape). Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analyses ​served to​ analyze target functional/pathway enrichment, while molecular docking validated SNG-core target binding. Experimentally, cell proliferation was assessed using Cell Counting Kit-8 and clonogenic assays. Apoptosis and autophagy were analyzed by flow cytometry, Western blot, and qRT-PCR. Computational pharmacology identified 16 principal molecular targets and emphasized the PI3K-AKT signaling pathway. SNG exhibited dose-responsive suppression of cellular viability and clonogenic capacity, alongside induction of apoptosis through BAX and BCL-2 regulation. Mechanistically, SNG triggered cytoprotective autophagy, evidenced by enhanced Beclin-1 expression, LC3-I to LC3-II conversion, and reduced p62 levels. Autophagy suppression markedly attenuated SNG’s anti-tumor activity. Moreover, SNG exhibited high binding affinity to key targets (ANXA5, STAT1, and Peroxisome Proliferator-Activated Receptor Gamma (PPARG)). Subsequent PPARG upregulation suppressed this critical oncogenic pathway. SNG exerts anti-neoplastic effects against NSCLC by promoting apoptosis and triggering cytoprotective autophagy, primarily through enhancing PPARG expression to suppress the PI3K-AKT signaling cascade.