NFAT3-high dysplastic clones drive IL-17C-mediated local epithelial remodeling and subtype-specific risk stratification in OPMDs

Abstract Objectives Malignant transformation (MT)-associated risk in oral potentially malignant disorders (OPMDs) involves not only dysplastic epithelial changes but also local remodeling of neighboring epithelium. Nuclear factor of activated T cells 3 (NFAT3) is a stress-responsive transcription factor, yet its role in early oral carcinogenesis and field cancerization-like processes remains unclear. This study investigated whether NFAT3-high dysplastic cells remodel adjacent epithelium via an interleukin-17C (IL-17C) axis and whether NFAT3/IL-17C patterns support subtype-specific clinical stratification in OPMDs. Methods NFAT3 expression was profiled in public datasets and validated in animal model and oral epithelial cell lines. 2D/3D direct co-culture tracked time-dependent population shifts. Transcriptomics, RT-qPCR, Western blotting, and ELISA assessed IL-17C/interleukin-17 receptor E (IL-17RE) signaling and NF-κB activation, with functional tests using IL-17C supplementation and IL-17C–IL-17RE blockade. A supplementary Lotka–Volterra model described proportion trajectories. In the UK Biobank (UKB) OPMDs cohort (n=6,197), oral cancer diagnosis status was used for subtype-specific NFAT3/IL-17C stratification and interaction analyses. Results NFAT3 was upregulated in precancerous lesions and promoted epithelial proliferation. In direct co-culture, NFAT3-high DOK cells triggered transcriptional convergence in neighboring NFAT3-low DOK cells via an IL-17C–IL-17RE/NF-κB–associated paracrine program, producing local remodeling consistent with a field cancerization-like process. Clinically, NFAT3/IL-17C showed subtype-specific stratification and interaction patterns in the UK Biobank cohort, with more informative risk grouping in oral leukoplakia (OLK) and discoid lupus erythematosus (DLE). Conclusions These findings identify an NFAT3-high dysplastic clone–driven, IL-17C–mediated paracrine remodeling mechanism and support the NFAT3/IL-17C axis as a potential biomarker for subtype-specific risk stratification and early clinical intervention in OPMDs.