Expressional and prognostic value of cytokine receptor-like factor 3 in liver hepatocellular carcinoma patients via integrated bioinformatics analyses and experiments

<h4>Background</h4>Liver hepatocellular carcinoma is a highly prevalent and lethal malignancy. The orphan cytokine receptor-like factor 3, although evolutionarily conserved and implicated in hematopoiesis and neuroprotection, remains poorly characterized in liver hepatocellular carcinoma.<h4>Objective</h4>To investigate the expression pattern of cytokine receptor-like factor 3 in liver hepatocellular carcinoma and its association with clinicopathological characteristics, prognosis, and potential biological functions through bioinformatics analysis.<h4>Methods</h4>Cytokine receptor-like factor 3 mRNA and protein expression in liver hepatocellular carcinoma were evaluated using the cancer genome atlas, human protein atlas, immunohistochemistry, and qPCR. The association of cytokine receptor-like factor 3 expression with prognosis and clinicopathological features was assessed using Kaplan-Meier survival analysis, Cox regression, logistic regression, and receiver operating characteristic curves. Potential functional pathways associated with cytokine receptor-like factor 3 were explored using gene ontology, Kyoto encyclopedia of genes and genomes, gene set enrichment analysis, and ssGSEA.<h4>Results</h4>Cytokine receptor-like factor 3 expression was significantly elevated in liver hepatocellular carcinoma tissues and correlated with poorer overall survival, disease-specific survival, and progression-free interval. High cytokine receptor-like factor 3 expression was associated with advanced T stage, pathologic stage, histologic grade, and elevated alpha-fetoprotein levels, and emerged as an independent prognostic factor. Receiver operating characteristic curve analysis suggested a potential diagnostic value for cytokine receptor-like factor 3 in distinguishing liver hepatocellular carcinoma tissues from normal tissues. Enrichment analysis indicated that genes correlated with cytokine receptor-like factor 3 are enriched in pathways such as PI3K/Akt, Wnt, and JAK/STAT, as well as immune-related processes. Notably, cytokine receptor-like factor 3 expression showed a strong positive correlation with Th2 cell infiltration.<h4>Conclusions</h4>This study reveals that cytokine receptor-like factor 3 is overexpressed in liver hepatocellular carcinoma and is associated with poor patient prognosis and immune infiltration. These findings suggest that cytokine receptor-like factor 3 may serve as a promising candidate prognostic biomarker and warrants further investigation as a potential immunotherapeutic target in liver hepatocellular carcinoma. The mechanistic hypotheses generated here provide a foundation for subsequent experimental validation.