〔Abstract〕 O bjective To elucidate the molecular mechanism by which prohibitin 2 (PHB2) mediates periodontitis-induced bone tissue inflammation through regulating the nuclear factor kappa B (NF-κB) signaling pathway and its role in irreversible alveolar bone resorption. Methods Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were used to detect the expression differences of inflammatory factors and PHB2 in healthy and inflamed alveolar bone tissues of mice i n vivo. In vitro, an inflammatory model was established using lipopolysaccharide (LPS)-induced a mouse calvaria-derived preosteoblastic cell line, subclone E1 (MC3T3-E1) cells. Western blot and qRT-PCR were used to clarify the regulatory relationship between PHB2 and inflammatory factors, and immunofluorescence staining was performed to observe changes in PHB2 subcellular localization. PHB2 overexpression plasmids were constructed using molecular cloning, and RNA interference was employed to knock down PHB2 expression to assess its regulatory role in inflammation. Based on RNA-seq data, differential expression analysis based on the negative binomial distribution, version 2 (DESeq2) was used for differential expression analysis, and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment along with gene ontology (GO) functional annotation were performed to identify key signaling pathways and differentially expressed genes. Results In the mouse periodontitis model, PHB2 expression was significantly upregulated in alveolar bone tissues. In the in vitro inflammatory cell model, PHB2 levels positively correlated with interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) levels, and its subcellular localization shifted during inflammation. RNA-seq data and the detection of the level of phosphorylation of p65 protein (p-p65) demonstrated that PHB2 exacerbated inflammatory responses through the NF-κB signaling pathway and was mechanistically linked to upregulation of the upstream chemokine C-X-C motif chemokine ligand 10 (CXCL10). C onclusion PHB2 aggravates LPS-induced periodontitis inflammation via the NF-κB signaling pathway, providing new insights into the molecular mechanisms underlying the development of periodontitis.