Pharmacological Targets for Periodontitis: A Systematic Review of Drug‐Target Mendelian Randomisation Studies

Abstract

ABSTRACT Aim Drug‐target Mendelian randomisation (MR) studies investigate whether genetically proxied modulation of druggable proteins affects the risk of periodontitis, thereby identifying potential pharmacological targets. Methods A systematic review was conducted following PRISMA 2020 guidelines. Three electronic databases (MEDLINE/Pubmed, Scopus, Web of Science) were searched. Eligible studies applied MR to evaluate causal relationships between druggable targets and periodontitis. Data on study design, population, exposure, and outcomes were extracted; risk of bias was assessed qualitatively. Supplementary searches of Google Scholar, reference lists, and medRxiv were also undertaken. Results Fifteen MR studies published between 2023 and 2026 were included. Underlying data on periodontal outcomes were derived from a limited number of studies. Identified targets spanned inflammatory cytokines (e.g., IL6R), complement components (C3 and C5), immune regulators (CXCL10 and CXCR4), calcium‐binding proteins (S100A8/A9/A12), and proteins involved in angiogenesis, apoptosis, cell‐cycle regulation, and extracellular‐matrix remodelling, including VEGFA, CASP3, CCND1, and MMP25. Several studies integrated multi‐omics, colocalization, and single‐cell approaches. However, the therapeutic relevance of these targets remains to be established through independent replication and experimental or clinical validation. Conclusion Drug‐target MR provides a platform for investigating host molecular traits linked to periodontal disease and highlights multiple targets for possible drug repurposing in the future. Methodological and data constraints currently limit the validity of these findings and their potential clinical applications.