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Periodontitis, a prevalent inflammatory disease, involves the destruction of tooth-supporting tissues. N6-methyladenosine (m6A) is a type of post-transcriptional modification that significantly influences gene and protein expression. It is involved in the regulation of various diseases, including those with an inflammatory component. This study investigates the potential role of m6A-mediated TREM-1 expression in the development of periodontitis. Clinical features and TREM-1 expression were assessed in periodontitis patients and healthy controls. LPS-stimulated human gingival fibroblasts (HGFs) were used to investigate m6A levels, m6A regulator METTL3, TREM-1, and inflammatory gene expression. In silico functional analysis explored TREM-1 interactions and functionalities. Periodontitis patients showed significantly elevated TREM-1 expression at both mRNA and protein levels. Predicted m6A motifs were present within the TREM-1 transcript. LPS stimulation of HGFs increased m6A content, METTL3, and TREM-1 expression, suggesting a potential link between m6A modification and TREM-1 regulation. Bioinformatic analysis revealed TREM-1 interaction with genes associated with periodontitis and its association with inflammatory pathways. This study suggests a potential role for METTL3-mediated m6A modification in regulating TREM-1 expression in periodontitis. Further investigation is needed to solidify this link and translate findings into clinical applications for improved periodontal health., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)