Melissa officinalis extract selectively suppresses STAT1 signaling in oral epithelial cells.

Oral inflammatory diseases such as oral lichen planus are characterized by dysregulated chemokine production and persistent interferon-associated signaling, with JAK/STAT pathways playing a central role in epithelial-immune crosstalk. Here, we investigated whether Melissa officinalis extract (MOE), a widely used phytomedicine with incompletely defined mechanisms, modulates inflammatory signaling in oral epithelial cells. MOE composition was characterized by HPLC-HRMS, and transcriptomic, RT-qPCR, ELISA, immunofluorescence, and cell-free kinase analyses were employed to define its biological effects in HSC2 and non-transformed epithelial cells. MOE was cytocompatible and selectively attenuated interferon-associated signaling rather than broadly suppressing inflammation. It markedly reduced interferon-stimulated gene expression, including MX1/2, IFIT and OAS family members, STAT1/2, CXCL10, and GBP1, while NF-κB-dependent CXCL8 expression remained unaffected. Mechanistically, MOE reduced JAK2 activity in a cell-free assay and suppressed STAT1 phosphorylation-associated nuclear translocation, supporting modulation of canonical interferon signaling. Consistently, MOE reduced CXCL10 expression at both mRNA and protein levels, and these effects occurred independently of reactive oxygen species modulation. Chemical profiling identified several phenolic acids, among which caffeic acid showed activity in suppressing CXCL10 production. These findings identify MOE as a pathway-selective modulator of interferon-driven inflammatory responses in oral epithelial cells, provide mechanistic insight into its clinical use, and support further investigation of Melissa officinalis-derived preparations as topical strategies for targeted modulation of mucosal inflammation.