OBJECTIVE: Versican (VCAN), a prominent extracellular matrix component upregulated in inflammatory diseases, demonstrates context-specific regulatory mechanisms. In periodontitis, a chronic inflammatory disease leading to periodontal tissue destruction and tooth loss, the pathological role of it remains poorly defined. Our study aims to examine VCAN-mediated mechanisms in periodontitis. METHODS: We conducted a comprehensive analysis of bulk RNA sequencing and single-cell RNA sequencing data to examine VCAN expression levels and sources in periodontitis. Functional and correlation analyses were used to explore its biological functions. We then validated VCAN expression using quantitative real-time polymerase chain reaction, immunohistochemical staining, and immunofluorescence staining in animal models and investigated its biological functions in inflammation through in vitro experiments. RESULTS: Our findings reveal that VCAN is mainly generated by fibroblasts in periodontitis, and its expression significantly upregulated at both mRNA and protein levels. Using VCAN-overexpressing L929 cells, we demonstrated enhanced proliferative capacity and inflammatory potential. Co-culture experiments with RAW264.7 cells showed promoted migration, adhesion, M1 polarization, and mitogen-activated protein kinase (MAPK) pathway activation. CONCLUSION: VCAN enhances fibroblast proliferation and migration, consequently elevating inflammatory factor production. Furthermore, fibroblast-derived VCAN not only induces macrophage chemotaxis, migration, adhesion, and polarization toward the proinflammatory M1 phenotype, but also activates MAPK signaling of macrophage, which may amplify inflammatory cascades to exacerbate periodontal tissue destruction. Targeted regulation of VCAN expression may become a promising precision treatment strategy for periodontitis.