Multi-omics and spatial transcriptomics identify KCMF1 as an immune-metabolic driver of hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, characterized by poor prognosis and limited treatment options. Ubiquitination, a key post-translational modification, plays crucial roles in cancer progression. However, the specific contribution of ubiquitination-associated genes to HCC remains largely unexplored. Public datasets from TCGA and GEO were analyzed to identify ubiquitination-associated genes (K48 and K63 ubiquitin chains). Prognostic models were constructed using multiple regression algorithms, consistently identifying KCMF1 as the top contributor. Bulk transcriptomic analysis was performed to assess differential expression, immune infiltration, and pathway enrichment. Single-cell and spatial transcriptomic analyses further investigated KCMF1's expression and its functional role in the tumor microenvironment. KCMF1 was significantly overexpressed in HCC tissues and strongly associated with poor overall and disease-specific survival. Transcriptomic analysis revealed its positive correlation with immune cell populations enriched in the tumor microenvironment, such as M0 macrophages (naive/precursor macrophages that serve as the cellular source for TAM polarization). Functional enrichment highlighted KCMF1's involvement in VEGF and TGFβ signaling pathways, which promote angiogenesis and immune suppression. Single-cell analysis identified KCMF1-positive malignant cells as hubs of intercellular communication, while spatial transcriptomics confirmed its enrichment in malignant regions, underscoring its role in tumor-stroma interactions. KCMF1 is a pivotal ubiquitination-associated gene that drives HCC progression through immune modulation. Integrative single-cell and spatial transcriptomics further locate KCMF1-enriched malignant niches, providing spatially resolved biomarker evidence. Its consistent prognostic relevance across analyses highlights its potential as a biomarker and therapeutic target. Therefore, KCMF1-directed therapy and combined immune-metabolic interventions warrant further investigation.