SEMA4F: A Spatially Specific Oncogenic Factor and Potential Therapeutic Target Identified in Hepatocellular Carcinoma

Objective Hepatocellular carcinoma (HCC) is a malignant tumor with high global incidence and mortality rates, characterized by complex pathogenesis and a lack of effective specific therapeutic targets. This study focuses on SEMA4F, a member of the Semaphorin family (previously known for its role in the nervous system), to explore its potential function and mechanisms in HCC.Methods Public databases (TCGA, ICGC, GEO, GEPIA) were utilized to analyze SEMA4F expression and its prognostic value in gastrointestinal tumors. Spatial transcriptomics and the HPA database were integrated to examine its tissue localization and relationship with the immune microenvironment. Gene Set Variation Analysis (GSVA) was employed to predict functional pathways associated with SEMA4F. SEMA4F was knocked down in HCC cell lines to assess its impact on cell proliferation.Results SEMA4F was significantly overexpressed in multiple gastrointestinal tumors, especially in HCC, where its high expression strongly correlated with poor prognosis and advanced clinical stages. Spatial transcriptomics and immunohistochemistry revealed tumor-specific overexpression of SEMA4F in HCC tissues, with its expression pattern linked to spatial distribution of immune cells. GSVA enrichment analysis demonstrated significant activation of multiple proliferation-related signaling pathways in SEMA4F-high HCC samples. In vitro functional experiments confirmed that SEMA4F knockdown markedly suppressed HCC cell proliferation and colony formation capacity.Conclusion SEMA4F exerts an oncogenic role in HCC, potentially by regulating proliferation-related pathways. Its tumor-specific overexpression, prognostic relevance, and pro-proliferative function highlight SEMA4F as a promising diagnostic/prognostic biomarker and therapeutic target for HCC.