Zinc Inversely Associates With Periodontitis Risk: An Exploratory Multi‐Omics Study Integrating Metallomics, Transcriptomics and Cellular Analyses

ABSTRACT Aim To examine the association between metal profiles in plasma and periodontitis and explore zinc's role in inflammatory pathways using multi‐omics and cellular approaches. Materials and Methods A case–control study including 424 individuals was conducted. Plasma levels of 35 metals were measured by inductively coupled plasma mass spectrometry. Logistic regression, Bayesian kernel machine regression, weighted quantile sum regression and quantile g‐computation were used to assess single‐ and mixed‐metal associations. Transcriptomics, network pharmacology and virtual knockout analyses explored inflammatory pathways related to reduced zinc. Cellular experiments using TPEN in hPDLFs provided exploratory biological context. Results Zinc showed the strongest inverse association with periodontitis (OR = 0.299, 95% CI: 0.185–0.446). Multi‐metal models consistently identified zinc as the primary inversely associated element (WQS weight = 0.690; g‐computation weight = −0.622). Multi‐omics analyses indicated enrichment of the NF‐κB/NLRP3 inflammasome pathway. Zinc chelation was associated with increased expression of IL1B , IL18 , NLRP3 , CASP1 and RELA in vitro. Virtual knockout analyses suggested the involvement of cytoskeleton regulation, integrin signalling and fibroblast transition. Conclusion This exploratory study supports an inverse association between plasma zinc and periodontitis in a multi‐metal context. Multi‐omics and cellular results are hypothesis‐generating only, and causal or preventive implications require confirmation from prospective and experimental studies.