〔Abstract〕 To elucidate the molecular mechanism by which prohibitin 2 (PHB2) mediates periodonti- tis-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 in- flammatory factors and PHB2 in healthy and inflamed alveolar bone tissues of mice in vivo . In vitro , an inflammato- ry 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 en- richment 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) dem- onstrated that PHB2 exacerbated inflammatory responses through the NF-κB signaling pathway and was mechanisti- cally linked to upregulation of the upstream chemokine C-X-C motif chemokine ligand 10 (CXCL10) . Conclusion PHB2 aggravates LPS-induced periodontitis inflammation via the NF-κB signaling pathway , providing new in- sights into the molecular mechanisms underlying the development of periodontitis .