JAK/STAT Signaling in Oral Lichen Planus: From Cytokine-Driven Immune Dysregulation to Barrier Dysfunction and Targeted Therapy

Oral lichen planus (OLP) is a chronic, immune-mediated condition in which the oral epithelium acts simultaneously as a target of cytotoxic injury and a driver of persistent mucosal inflammation. This narrative review examines Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling as a network of cell- and cytokine-dependent signaling modules rather than a single linear pathway. Human OLP tissues show elevated expression of JAK1, phosphorylated JAK1, and various STAT-family proteins across both epithelial and inflammatory compartments. Functional modules demonstrate that IFN-γ–JAK1/JAK2–STAT1 sensitizes basal keratinocytes to cytotoxic attack, while JAK2/STAT3 regulates epithelial survival, tight-junction integrity, and E-cadherin/CD103-dependent intraepithelial lymphocyte retention. Additionally, metabolic and redox inputs converge on the STAT3–CCL5 axis to reinforce T-cell recruitment, with spatial analyses placing cytotoxic T cells directly at the epithelial interface. Although clinical responses to targeted JAK inhibitors (including JAK1, JAK1/2, JAK1/3, JAK3/TEC, and TYK2 agents) are encouraging, most current evidence remains observational. Because inhibitor selectivity is relative, therapeutic efficacy alone cannot identify the primary upstream cytokine driver. Advancing OLP management requires moving beyond broad pathway inhibition toward spatially resolved phospho-endotyping linked with standardized clinical phenotypes, mechanistic biomarkers, and targeted local therapies to enable a true precision treatment strategy.