PSMD4 promotes malignant phenotypes and is associated with angiogenesis-related signaling and immune remodeling in hepatocellular carcinoma

BACKGROUND: Proteasome 26 S non-ATPase subunit 4 (PSMD4) is implicated in various cancers, but its role in hepatocellular carcinoma (HCC) is unclear. This study investigates PSMD4 expression, prognostic value, and functions in HCC progression, angiogenesis, and immune regulation. METHODS: TCGA-LIHC was used as the training cohort and ICGC-LIRI as an external validation cohort to assess PSMD4 expression and prognostic value. Human Protein Atlas (HPA) immunohistochemistry data were used to evaluate PSMD4 protein expression. Survival, ROC, nomogram, functional enrichment, immune infiltration, single-cell, and cell-cell communication analyses were performed. Single-cell RNA-seq data from GSE146409 were used to assess cell-type-specific PSMD4 expression and intercellular communication patterns. Spatial transcriptomics data from HRA000437 were used to visualize the spatial distribution of PSMD4 expression in HCC tissues. The biological role of PSMD4 was validated in Huh7 and HepG2 cells using qRT-PCR, CCK-8, colony formation, wound-healing, and western blot assays. RESULTS: PSMD4 was significantly upregulated in HCC in both TCGA-LIHC and ICGC-LIRI cohorts, with positive protein expression confirmed by HPA immunohistochemistry. High PSMD4 expression was associated with poorer overall survival and showed moderate predictive performance for survival outcomes. Enrichment analyses linked PSMD4 to cell-cycle progression, DNA replication, genomic instability, and angiogenesis-related pathways. Single-cell analysis indicated that PSMD4 was mainly enriched in malignant hepatocytes and SPP1⁺ tumor-associated fibroblasts, while spatial transcriptomics analysis showed that PSMD4 expression was concentrated in tumor-dense regions. PSMD4 knockdown inhibited HCC cell proliferation, colony formation, and migration, and reduced VEGFA, RAF1, and MEK1/2 expression. Moreover, high PSMD4 expression was associated with decreased antitumor immune infiltration and suppression of immune activation-related genes. CONCLUSION: PSMD4 is upregulated in HCC and is associated with unfavorable prognosis. Functional assays suggest that PSMD4 contributes to malignant phenotypes and angiogenesis-related signaling in HCC cells, while computational immune analyses indicate an association between high PSMD4 expression and an immunosuppressive immune landscape. These findings suggest that PSMD4 may serve as a potential prognostic biomarker and candidate therapeutic target in HCC.