SOCS2 mediates JAK2/STAT3 signaling and enhances ferroptosis and sorafenib sensitivity in hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) remains among the leading causes of cancer-related mortality worldwide, and its epidemiological burden continues to expand because of persistently increasing incidence and death rates. Emerging evidence suggests that ferroptosis participates in hepatocarcinogenesis, treatment responsiveness, and disease progression. Accordingly, this study sought to screen for ferroptosis-related biomarkers that may possess diagnostic value in hepatocellular carcinoma and to further elucidate their functional relevance and clinical significance. Methods Transcriptomic datasets from five independent HCC cohorts were obtained from the Gene Expression Omnibus (GEO) repository. Differential expression analysis was performed to identify shared genes, followed by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Candidate biomarkers were screened using least absolute shrinkage and selection operator (LASSO) regression. Ferroptosis-associated genes collected from the FerrDb database were integrated with common differentially expressed genes to determine overlapping targets. The TCGA-LIHC was subsequently utilized as an external validation dataset to evaluate diagnostic efficacy. Immune infiltration patterns associated with SOCS2 expression were characterized through combined ssGSEA and CIBERSORT analyses. Hallmark was further conducted to assess the potential signaling mechanisms involving SOCS2. Functional experiments in vitro were subsequently performed to verify the relationship between SOCS2 and ferroptosis. Result 71 common differentially expressed genes were identified across the included datasets. Functional analyses demonstrated that these genes participated in several biologically important pathways. By integrating LASSO regression with ferroptosis-related gene profiles, CDC20 and SOCS2 were recognized as potential hub genes. Validation in the TCGA-LIHC revealed that SOCS2 displayed stronger associations with canonical ferroptosis markers than CDC20. SOCS2 abundance was substantially reduced in HCC specimens, and diminished expression was correlated with unfavorable prognosis and more advanced histological grade. Immune infiltration analyses indicated significant correlations between SOCS2 and multiple immune cell subsets, implying a role in immune regulatory networks. Experimental studies further demonstrated that enforced SOCS2 expression promoted ferroptotic responses in HCC cells, an effect that may be attributable to altered JAK2/STAT3 pathway activity. CONCLUSIONS The present findings suggest that SOCS2 is closely involved in ferroptosis regulation and immune-related processes in HCC, providing additional insights into the molecular mechanisms underlying HCC progression.