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

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 ident...

Full description

Saved in:
Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: Springer Nature 2025-06-01
Series:EMBO Molecular Medicine
Subjects:
Oral Leukoplakia
Photodynamic Therapy
Resistance
NRF2
WNT
Online Access:https://doi.org/10.1038/s44321-025-00256-w
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1757-4684

Similar Items