Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 0 0 2026 05 19 1 15 Guifang Jiang Clinical Laboratory, Huzhou Wuxing District People’s Hospital, Huzhou Wuxing District Maternal and Child Health Hospital, Huzhou, China Junping Pan Laboratory, Huzhou Wuxing District Center for Disease Prevention and Control (Wuxing District Health Supervision Institute), Huzhou, China 2026 01 01 2026 02 08 Progression from chronic hepatitis B (CHB) to cirrhosis is closely associated with immune dysregulation and altered cytokine signaling, yet effective noninvasive immune biomarkers remain limited. This study aimed to develop a peripheral blood mononuclear cell (PBMC)-based cytokine gene signature for predicting HBV-related cirrhosis. The GSE114783 microarray dataset was analyzed to identify differentially expressed genes between CHB and cirrhosis. Immune-related candidate genes were selected by integrating curated immune resources and the Kyoto Encyclopedia of Genes and Genomes cytokine-cytokine receptor interaction pathway. Least absolute shrinkage and selection operator regression and multivariable logistic regression were used to construct the predictive model. Receiver operating characteristic analysis, leave-one-out cross-validation, and nomogram development were performed to evaluate model performance and support clinical translation. Differential expression analysis identified 3169 genes distinguishing cirrhosis from CHB, from which 86 immune/cytokine-related genes were prioritized. LASSO selected a parsimonious 4-gene signature-CXCR1, IL11RA, IL13RA2, and CD19-capturing key immune axes relevant to chronic inflammation and fibrogenesis (chemokine receptor signaling, IL-11/IL-13 receptor pathways, and B-cell–associated immunity). The resulting model achieved an area under the curve (AUC) of 0.935 (95% CI, 0.882-0.988); at an optimal cutoff of 0.832, sensitivity was 88.6% and specificity 84.3%. LOOCV supported robust performance, and the nomogram demonstrated good agreement between predicted and observed risk. A PBMC-based immune cytokine-receptor gene signature (CXCR1/IL11RA/IL13RA2/CD19) provides a noninvasive tool for immunologically informed risk stratification of HBV-related cirrhosis and may support immune monitoring and early intervention strategies. Prospective, multicohort validation and mechanistic studies are warranted. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4729 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4729/2344