Yanqing Liu, Xiaomeng Xue, Zhaorong Li, Ziming Ge, Muzhou Jiang, Jingbo Liu, Y P Pan, Li Li
Abstract This study investigated the relationship between periodontitis and metabolic dysfunction-associated steatotic liver disease (MASLD), with a specific focus on the role of Porphyromonas gingivalis peptidylarginine deiminase (PPAD) carried by P. gingivalis -derived outer membrane vesicles (OMVs) in hepatic lipid metabolism. Clinical analyses revealed a positive correlation between periodontal disease severity and the fatty liver index (OR = 6.18, 95% CI: 2.36–16.13), a predictor of MASLD. In an obese mouse model of periodontitis, P. gingivalis -induced periodontitis accelerated MASLD progression, promoted hepatic lipid accumulation and increased inflammation. Since P. gingivalis OMVs had the advantage of traveling through the blood to the liver, we found that they demonstrated liver-specific accumulation, impairing fatty acid oxidation and increasing lipid deposition in hepatocytes, when injected into MASLD model mice via the tail vein. The critical role of PPAD was confirmed using the P. gingivalis Δppad and P. gingivalis ppad−oe strains, from which OMVs were isolated. The results of the in vivo and in vitro experiments indicated that PPAD-enriched OMVs mediated hepatic metabolic dysregulation via suppression of the circadian regulator NPAS2 and downstream inhibition of CYP4A10 expression, revealing a previously unrecognized PPAD–liver communication pathway. These findings highlight the urgent need for effective PPAD inhibitors and a deeper understanding of the interactions of PPAD with host proteins implicated in systemic diseases, underscoring the broader health impacts of periodontal disease. Graphical Abstract