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

## TL;DR

This study identifies a shared inflammatory network linking type 2 diabetes and hepatitis B infection to bile duct cancer progression, offering new insights for prevention and treatment.

## Contribution

The study reveals a conserved metaflammation gene network connecting T2D, HBV, and cholangiocarcinoma, with key hub genes linked to patient survival.

## Key findings

- A core metaflammation network of 156 genes was identified, linking T2D, HBV, and cholangiocarcinoma.
- Five key genes (IL6, TNF, AKT1, STAT3, PPARG) were found to correlate with advanced tumor stage and poor survival.
- A metaflammation score based on these genes emerged as an independent prognostic factor for cholangiocarcinoma patients.

## Abstract

Cholangiocarcinoma, a malignancy of the bile ducts, is associated with poor survival, and its incidence is rising globally. This trend parallels the rising epidemics of type 2 diabetes mellitus and chronic hepatitis B infection. Although these conditions are recognized risk factors for cancer, the underlying biological mechanisms remain poorly understood. In this study, we conducted an integrative analysis of genetic data from patients with these three diseases to identify potential molecular links. Our analysis revealed a shared set of 156 genes, implicating a state of chronic inflammation driven by metabolic dysregulation that connects diabetes and hepatitis B infection to cholangiocarcinogenesis. Within this network, five key genes were significantly associated with patient survival. These findings provide a molecular framework that elucidates how these risk factors contribute to cancer development. This research opens new avenues for identifying at-risk individuals and suggests that targeting this specific inflammatory pathway may offer novel strategies for cancer prevention and treatment.

Background and Aims: The rising global incidence of cholangiocarcinoma (CCA) coincides with epidemics of type 2 diabetes (T2D) and chronic hepatitis B virus (HBV) infection. Although both are established independent risk factors, the shared molecular mechanisms by which they contribute to cholangiocarcinogenesis remain poorly understood. 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, including samples of CCA (TCGA-CHOL, n = 45; GSE107943, n = 163), T2D-affected liver (GSE23343, n = 20), and HBV-infected liver (GSE58208, n = 102). Acknowledging that the T2D and HBV datasets were derived from whole-liver tissue, whereas CCA originates in the biliary epithelium, we identified differentially expressed genes (DEGs) across conditions and defined a core gene set shared among them. Subsequent analyses included functional enrichment, construction of protein–protein interaction (PPI) networks, survival analysis, and protein validation. 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. Protein–protein interaction (PPI) network analysis identified IL6, TNF, AKT1, STAT3, and PPARG as the top hub genes. These hubs were functionally modularized into clusters associated with inflammatory signaling, metabolic regulation, and cell growth and 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 poorer overall survival (e.g., IL6: ρ = 0.42, p = 0.01). A metaflammation score derived from these hubs (weighted combination of the five genes) emerged as an independent prognostic factor (HR = 2.8, p < 0.001). Protein-level dysregulation of these hubs was confirmed via immunohistochemistry. Conclusions: This study defines a conserved metaflammation network that links 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 in prevention and therapy for high-risk populations.