Fumarate-associated immunometabolic network in Periodontitis revealed by integrated transcriptomic and single-cell RNA sequencing analysis

Periodontitis is a long-term inflammatory disease of the gums that damages the tissues and bone supporting the teeth. Recent studies suggest that changes in cellular metabolism may influence immune responses during chronic inflammation; however, the contribution of fumarate-associated transcriptional programs to periodontitis remains unclear. In this study, we integrated bulk transcriptomic data from human periodontal tissues with single-cell RNA sequencing data to identify fumarate-associated genes and cell clusters associated with periodontitis. Our analyses revealed a fumarate-associated immune regulatory signature that was enriched in periodontitis. Three genes, C3 , CXCR4 , and MEF2C , were consistently increased in diseased tissues and showed similar expression trends in a ligature-induced mouse model of periodontitis. These genes showed transcript-level diagnostic potential and were predominantly expressed in immune cells, including myeloid cells and neutrophils, as well as stromal cells. In addition, computational drug screening and molecular docking highlighted carbenoxolone and a CXCR4 antagonist (USL311) as potential candidates for future study. Overall, this study provides an integrative view of fumarate-associated immunometabolic alterations in periodontitis and identifies candidate transcriptomic markers and therapeutic hypotheses that warrant further experimental validation.