Multi-omics integration reveals ANXA6-high γδ T cell-endothelial communication as a potential link between periodontitis and MASLD.

Periodontitis (PD) and metabolic dysfunction-associated steatotic liver disease (MASLD) were highly prevalent inflammatory disorders that frequently coexisted, yet the molecular basis of their comorbidity remained poorly defined. Here, we applied an integrative multi-omics strategy that combined bulk RNA sequencing, weighted gene co-expression network analysis, spatial transcriptomics, single-cell profiling, and machine learning. This approach identified 11 hub genes bridging immune activation and metabolic remodeling, among which Annexin A6 (ANXA6) emerged as a key cross-disease candidate. Spatial transcriptomics supported tissue-specific localization of the hub-gene signature, while single-cell analysis revealed selective enrichment of ANXA6 expression in γδ T cells. Notably, ANXA6-high γδ T cells exhibited enhanced signaling interactions with endothelial cells, suggesting immune-vascular crosstalk in PD-MASLD comorbidity. Upstream regulatory analysis further highlighted transcription factors associated with ANXA6 expression, and Connectivity Map-based prediction suggested candidate compounds with the potential to reverse ANXA6-associated transcriptional programs. Collectively, these findings support the hypothesis that ANXA6-high γδ T cell-endothelial communication represents a shared immunological feature of PD-MASLD comorbidity, offering novel insights into common immune programs and potential therapeutic opportunities.