Integrated Multi-Omics Analysis Reveals Cytokine Network Dynamics and Prognostic Signatures in Hepatitis B Virus-Associated Hepatocellular Carcinoma.

Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) remains a major global health challenge due to late diagnosis and high tumor heterogeneity. Cytokines, as key mediators of the tumor microenvironment, contribute to immune evasion and tumor progression in HBV-HCC. However, their prognostic significance remains unclear. Bulk RNA sequencing revealed differentially expressed cytokine genes in HBV-HCC. A cytokine-based gene signature was created using the LASSO model, and Single-cell RNA sequencing analyzed gene expression at the cellular level. Serum and in vitro assays confirmed the key cytokine's role in tumor progression. Ten cytokine genes were differentially expressed in HBV-HCC, and six (CCL19, CCL20, CXCL2, GHR, IL1RAP, and LIFR) were selected to construct the LASSO-based risk model. This six-cytokine signature stratified patients into high- and low-risk groups with significantly different overall survival (P < 0.0001), achieving an area under the curve (AUC) exceeding 0.7 for 3-year survival in both training and validation cohorts. scRNA-seq revealed distinct cellular expression patterns of these cytokines, providing insights into their roles in tumor heterogeneity. High-risk patients exhibited enriched cell proliferation pathways and pronounced immunosuppression, whereas low-risk patients were associated with metabolic pathways. Drug sensitivity analysis identified 61 differentially responsive antitumor agents between risk groups. Notably, serum GHR levels increased during fibrosis but declined significantly in HBV-HCC. Functional assays demonstrated that GHR overexpression suppressed proliferation, migration, and invasion while promoting apoptosis. Our study integrates bulk and single-cell transcriptomics with functional validation, unveiling cytokine-driven mechanisms in HBV-HCC. The cytokine-based prognostic model holds promise for risk stratification, immunomodulation, and personalized therapy, offering new avenues for improving HBV-HCC management.