2. Academic Validation
  3. NRF2 modulates WNT signaling pathway to enhance photodynamic therapy resistance in oral leukoplakia

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

  • EMBO Mol Med. 2025 Jul;17(7):1794-1824. doi: 10.1038/s44321-025-00256-w.
Tiantian Xu # 1,  Liang Zhong # 2,  Qianxi Liu # 1,  Fei Wang # 1,  Wenjing Kuang 1,  Jiaqi Liang 1,  Dan Yang 1,  Xikun Zhou 3,  Hongxia Dan 1,  Hang Zhao 1,  Taiwen Li 4,  Xin Zeng 5,  Jing Li 6,  Qianming Chen 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 2 Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center of Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
  • 4 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China. litaiwen@scu.edu.cn.
  • 5 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China. zengxin@scu.edu.cn.
  • 6 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China. lijing1984@scu.edu.cn.
  • # Contributed equally.
PMID: 40494896 DOI: 10.1038/s44321-025-00256-w
Abstract

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.

Keywords

NRF2; Oral Leukoplakia; Photodynamic Therapy; Resistance; WNT.

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