Type I Interferon induces Keratinocytes Necroptosis via the ZBP1-MLKL Axis in Oral Lichen Planus

Abstract Oral lichen planus (OLP) is a prevalent chronic inflammatory condition that affects the oral mucosa. Histologically, it is characterized by the liquefaction and degeneration of basal epithelial cells, indicating a disruption of the basal layer architecture, which may represent an early event in the disease’s pathogenesis. However, the molecular mechanisms underlying this epithelial damage remain poorly understood. In our study, histological staining and transmission electron microscopy revealed aberrant cell death in the basal epithelial layer of OLP tissues. Immunodetection demonstrated the presence of phosphorylated mixed lineage kinase domain-like protein (pMLKL), a key marker of necroptosis, specifically localized to basal keratinocytes. Notably, interferon type I (IFN-I), particularly IFNα, was significantly upregulated in OLP mucosa compared to healthy controls. The expression of Z-DNA binding protein 1 (ZBP1), an IFN-stimulated gene and an upstream regulator of necroptosis, was elevated in pMLKL-positive epithelial cells. In vitro stimulation with IFNα2a induced the expression of ZBP1 and pMLKL in HaCaT keratinocytes, while ZBP1 knockdown abrogated MLKL phosphorylation. Collectively, these results suggest that, in the context of increased IFN-I signaling, ZBP1 is aberrantly upregulated in the OLP epithelium, promoting necroptosis in basal keratinocytes. This necroptotic activity may contribute to the damage and disruption of the basal layer, providing novel insights into the pathogenesis of OLP and highlighting potential molecular targets for therapeutic intervention.