Systems-Level Transcriptomic Integration Reveals a Core Metaflammatory Network Linking Type 2 Diabetes and HBV Infection to Cholangiocarcinoma Progression

Background & Aims The rising global incidence of cholangiocarcinoma (CCA) coincides with epidemics of type 2 diabetes (T2D) and chronic Hepatitis B virus (HBV) infection. While both are established independent risk factors, the shared molecular mechanisms underlying their contribution to cholangiocarcinogenesis remain poorly defined. We hypothesized that T2D and HBV converge on a state of chronic metabolic inflammation ("metaflammation") that drives CCA progression through a conserved transcriptomic network. Methods We performed an integrative bioinformatics analysis of transcriptomic data from public repositories representing CCA (TCGA-CHOL, n=45; GSE107943, n=163), T2D-affected liver (GSE23343, n=20), and HBV-infected liver (GSE58208, n=102). We identified differentially expressed genes (DEGs), defined a cross-condition core gene set, and conducted functional enrichment, protein-protein interaction (PPI) network, survival, and protein validation analyses. Results We identified a core metaflammation signature comprising 156 genes that were consistently dysregulated across T2D, HBV, and CCA. Pathway analysis revealed significant enrichment in PPAR signaling, cytokine-cytokine receptor interaction, PI3K-Akt, and TNF signaling pathways. PPI network analysis identified IL6, TNF, AKT1, STAT3, and PPARG as top hub genes. These hubs were functionally modularized into clusters for inflammatory signaling, metabolic regulation, and cell growth/survival. In the TCGA CCA cohort, high expression of IL6, TNF, AKT1, and STAT3, and low expression of PPARG, correlated with advanced tumor stage and poor overall survival (e.g., IL6 ρ = 0.42, P = 0.01). A derived metaflammation score (weighted combination of the five hubs) was an independent prognostic factor (HR=2.8, P< 0.001). Protein-level dysregulation of these hubs was confirmed by immunohistochemistry. Conclusions This study defines a conserved metaflammatory network linking T2D and HBV to CCA, identifying key hub genes and pathways. This signature provides a mechanistic explanation for epidemiological risks, serves as a novel prognostic tool, and offers a rationale for targeting metaflammation for prevention and therapy in high-risk populations.