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<p>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for novel and effective therapeutic strategies. Avicularin (Avi), a naturally occurring flavonoid, has been shown to reduce cell viability and induce caspase-dependent apoptosis in NSCLC cells, while exhibiting minimal cytotoxicity toward normal bronchial epithelial cells. Mechanistically, Avi selectively decreases FOXM1 protein expression without affecting its mRNA levels, suggesting post-transcriptional regulation. Further investigation revealed that Avi promotes K48-linked polyubiquitination of FOXM1 and disrupts its interaction with the deubiquitinase USP7, thereby destabilizing FOXM1 and enhancing apoptotic signaling. Notably, overexpression of either FOXM1 or USP7 attenuated Avi-induced cytotoxicity. In vivo, Avi markedly inhibited tumor growth in A549 xenograft models without inducing systemic toxicity. Moreover, Avi enhanced the anti-tumor effects of gefitinib, leading to greater apoptosis and reduced cell viability compared to either agent alone. Collectively, these findings demonstrate that Avi exerts potent anti-NSCLC activity by facilitating USP7-dependent degradation of FOXM1 and highlight its potential as both a monotherapy and an adjuvant to EGFR-targeted therapies.</p>

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Avicularin induces apoptosis in NSCLC by promoting USP7-mediated degradation of FOXM1

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Jiangyue Du,
  • Kuai Yu,
  • Jian Zeng,
  • Lijuan Ma,
  • Tingting Yu,
  • Rui Yu,
  • Taobo Luo

摘要

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for novel and effective therapeutic strategies. Avicularin (Avi), a naturally occurring flavonoid, has been shown to reduce cell viability and induce caspase-dependent apoptosis in NSCLC cells, while exhibiting minimal cytotoxicity toward normal bronchial epithelial cells. Mechanistically, Avi selectively decreases FOXM1 protein expression without affecting its mRNA levels, suggesting post-transcriptional regulation. Further investigation revealed that Avi promotes K48-linked polyubiquitination of FOXM1 and disrupts its interaction with the deubiquitinase USP7, thereby destabilizing FOXM1 and enhancing apoptotic signaling. Notably, overexpression of either FOXM1 or USP7 attenuated Avi-induced cytotoxicity. In vivo, Avi markedly inhibited tumor growth in A549 xenograft models without inducing systemic toxicity. Moreover, Avi enhanced the anti-tumor effects of gefitinib, leading to greater apoptosis and reduced cell viability compared to either agent alone. Collectively, these findings demonstrate that Avi exerts potent anti-NSCLC activity by facilitating USP7-dependent degradation of FOXM1 and highlight its potential as both a monotherapy and an adjuvant to EGFR-targeted therapies.