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<p>Epithelial ovarian cancer (EOC), the deadliest gynecological malignancy, is increasingly linked to dysregulated lipid metabolism. Nevertheless, the involvement of circulating low-density lipoprotein (LDL) in ovarian cancer progression remains controversial. Analyses of single-cell RNA sequencing and clinical data demonstrated a positive correlation between elevated LDL levels and EOC progression. Mechanistically, LDL internalized via LDL receptor (LDLR) enhanced epithelial-mesenchymal transition (EMT) and stemness in ovarian cancer cells, driven by the upregulation of the key transcription factor FOXQ1. Intriguingly, our investigations unveiled a novel transcriptional complex comprising FOXQ1/β-Catenin/ADNP. Both β-Catenin and ADNP interacted with FOXQ1 at the Forkhead domain, where FOXQ1 bound to the NF-κB1 gene promoter to enhance transcriptional activation. Notably, β-Catenin and ADNP were identified for the first time as competitive repressors within this regulatory axis. These findings were further corroborated in vivo using an ovarian cancer xenograft metastasis model, as well as in human pathological specimens, highlighting LDL-driven metastasis via FOXQ1 upregulation. Collectively, LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. Furthermore, we discover a novel transcriptional complex, where FOXQ1 acts as the central regulator while β-Catenin/ADNP serve as co-repressors. These insights suggest that modulating serum LDL levels or targeting FOXQ1 may offer promising strategies to curb ovarian cancer progression.</p><p></p>

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High serum LDL promotes EMT and stemness through LDLR/FOXQ1/NF-κB1 pathway in epithelial ovarian cancer

  • 期刊论文

  • 发表日期：

    2025年10月22日

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  • Song Tang,
  • Kelie Chen,
  • Fang Zheng,
  • Zhiqin Fu,
  • Yuequn Niu,
  • Xinxin Liu,
  • Heng Ni,
  • Xiaoyu Yuan,
  • Zhenyan Cui,
  • Weiguo Lu,
  • Dajing Xia,
  • Yihua Wu

摘要

Epithelial ovarian cancer (EOC), the deadliest gynecological malignancy, is increasingly linked to dysregulated lipid metabolism. Nevertheless, the involvement of circulating low-density lipoprotein (LDL) in ovarian cancer progression remains controversial. Analyses of single-cell RNA sequencing and clinical data demonstrated a positive correlation between elevated LDL levels and EOC progression. Mechanistically, LDL internalized via LDL receptor (LDLR) enhanced epithelial-mesenchymal transition (EMT) and stemness in ovarian cancer cells, driven by the upregulation of the key transcription factor FOXQ1. Intriguingly, our investigations unveiled a novel transcriptional complex comprising FOXQ1/β-Catenin/ADNP. Both β-Catenin and ADNP interacted with FOXQ1 at the Forkhead domain, where FOXQ1 bound to the NF-κB1 gene promoter to enhance transcriptional activation. Notably, β-Catenin and ADNP were identified for the first time as competitive repressors within this regulatory axis. These findings were further corroborated in vivo using an ovarian cancer xenograft metastasis model, as well as in human pathological specimens, highlighting LDL-driven metastasis via FOXQ1 upregulation. Collectively, LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. Furthermore, we discover a novel transcriptional complex, where FOXQ1 acts as the central regulator while β-Catenin/ADNP serve as co-repressors. These insights suggest that modulating serum LDL levels or targeting FOXQ1 may offer promising strategies to curb ovarian cancer progression.