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<p>Oral leukoplakia (OLK) is a common potentially malignant oral disorder with high risk of malignant transformation. While photodynamic therapy (PDT) offers a minimally invasive treatment for OLK, some patients show resistance to PDT and the mechanisms remain unclear. This study aims to identify key regulatory pathways driving PDT resistance in OLK. Single-cell RNA sequencing of OLK samples (three PDT-sensitive, three PDT-resistant) revealed significant NRF2 upregulation in resistant tissues. Validation across two independent cohorts (<i>n</i> = 117) confirmed that p-NRF2 levels were significantly elevated in PDT-resistant cases, exhibiting strong predictive power for treatment response (AUC &gt; 0.8). Mechanistically, NRF2 promotes <i>CTNNB1</i> transcription, activates WNT signaling, modulates reactive oxygen species responses, and regulates keratinization, collectively contributing to PDT resistance. In a 4NQO-induced OLK mouse model, NRF2 inhibition combined with PDT effectively reversed OLK lesions and restored mucosal histology. These findings establish p-NRF2 as a valuable biomarker for guiding PDT regimens in OLK patients, reveal NRF2’s role in mediating PDT resistance via the WNT signaling pathway, and highlight NRF2 inhibition as a promising strategy to enhance PDT efficacy.</p>

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NRF2 modulates WNT signaling pathway to enhance photodynamic therapy resistance in oral leukoplakia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Tiantian Xu,
  • Liang Zhong,
  • Qianxi Liu,
  • Fei Wang,
  • Wenjing Kuang,
  • Jiaqi Liang,
  • Dan Yang,
  • Xikun Zhou,
  • Hongxia Dan,
  • Hang Zhao,
  • Taiwen Li,
  • Xin Zeng,
  • Jing Li,
  • Qianming Chen

摘要

Oral leukoplakia (OLK) is a common potentially malignant oral disorder with high risk of malignant transformation. While photodynamic therapy (PDT) offers a minimally invasive treatment for OLK, some patients show resistance to PDT and the mechanisms remain unclear. This study aims to identify key regulatory pathways driving PDT resistance in OLK. Single-cell RNA sequencing of OLK samples (three PDT-sensitive, three PDT-resistant) revealed significant NRF2 upregulation in resistant tissues. Validation across two independent cohorts (n = 117) confirmed that p-NRF2 levels were significantly elevated in PDT-resistant cases, exhibiting strong predictive power for treatment response (AUC > 0.8). Mechanistically, NRF2 promotes CTNNB1 transcription, activates WNT signaling, modulates reactive oxygen species responses, and regulates keratinization, collectively contributing to PDT resistance. In a 4NQO-induced OLK mouse model, NRF2 inhibition combined with PDT effectively reversed OLK lesions and restored mucosal histology. These findings establish p-NRF2 as a valuable biomarker for guiding PDT regimens in OLK patients, reveal NRF2’s role in mediating PDT resistance via the WNT signaling pathway, and highlight NRF2 inhibition as a promising strategy to enhance PDT efficacy.