Multiomics Reveals IL-17 Drives Epithelial Keratinization and Proliferation via EHF in Odontogenic Keratocysts

This study aims to investigate epithelial cell (EpC) heterogeneity in odontogenic keratocysts (OKCs) and the molecular mechanisms driving their characteristic keratinization and rapid proliferation. We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to profile OKC EpCs, validating findings via immunostaining and comparative analysis with normal oral mucosa. The regulatory roles of interleukin-17 (IL-17) and the transcription factor EHF were functionally assessed in vitro using human oral keratinocytes. Multi-omics mapping identified a distinct epithelial subpopulation (EpC2) characterized by robust keratinization, elevated keratin 13 (KRT13), and upregulated IL-17 signaling. Clinical OKC tissues exhibited significant upregulation and spatial co-localization of IL-17 and KRT13. In vitro, IL-17 robustly promoted cellular proliferation and KRT13 expression. Regulon analysis pinpointed EHF as the core transcription factor driving EpC2. EHF knockdown suppressed proliferation and downregulated KRT13, while overexpression amplified these processes. Crucially, IL-17 stimulation failed to rescue KRT13 expression in EHF-depleted cells, suggesting EHF as a critical downstream mediator. We present a comprehensive single-cell and spatial transcriptomic atlas of the OKC epithelium. The IL-17/EHF signaling axis appears to be a fundamental driver of OKC pathogenesis, promoting pathological hyperkeratinization and cellular proliferation. Targeting this axis presents a promising therapeutic strategy to manage OKC growth and prevent recurrence.