Xu Tiantian, Zhong Liang, Liu Qianxi, Wang Fei, Kuang Wenjing, Liang Jiaqi, Yang Dan, Zhou Xikun, Dan Hongxia, Zhao Hang, Li Taiwen, Zeng Xin, Li Jing, Chen Qianming
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.
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.
EMBO Mol Med. 2025 Jun 10. doi: 10.1038/s44321-025-00256-w.
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.
口腔白斑（OLK）是一种常见的具有恶变高风险的潜在恶性口腔疾病。虽然光动力疗法（PDT）为OLK提供了一种微创治疗方法，但一些患者对PDT表现出耐药性，其机制尚不清楚。本研究旨在确定导致OLK中PDT耐药的关键调控途径。对OLK样本（3例对PDT敏感，3例对PDT耐药）进行单细胞RNA测序，结果显示耐药组织中NRF2显著上调。在两个独立队列（n = 117）中进行的验证证实，在PDT耐药病例中p-NRF2水平显著升高，对治疗反应具有很强的预测能力（AUC > 0.8）。从机制上讲，NRF2促进CTNNB1转录，激活WNT信号，调节活性氧反应，并调节角化，共同导致PDT耐药。在4NQO诱导的OLK小鼠模型中，NRF2抑制与PDT联合使用可有效逆转OLK病变并恢复黏膜组织学。这些发现确立了p-NRF2作为指导OLK患者PDT治疗方案的有价值生物标志物，揭示了NRF2通过WNT信号通路介导PDT耐药的作用，并强调NRF2抑制作为提高PDT疗效的一种有前景的策略。
