Prognostic and therapeutic implications of PSMD14 in hepatocellular carcinoma: an integrative analysis of transcriptomic and single-cell profiles.

Background: Liver hepatocellular carcinoma (LIHC) represents a common and aggressive malignancy characterized by an unfavorable clinical outcome, highlighting an urgent need to discover reliable prognostic indicators and novel therapeutic targets. The present investigation centers on the JAMM family genes, with a specific emphasis on PSMD14, to delineate their functional contributions in the context of LIHC. Methods: We utilized an integrated analytical framework, incorporating bulk RNA sequencing data from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing (scRNA-seq) datasets, to systematically investigate the expression profiles, prognostic significance, and underlying functional roles of JAMM family deubiquitinases in LIHC. A prognostic risk score model was developed through least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. To elucidate the biological functions and signaling pathways linked to PSMD14, we performed comprehensive functional enrichment analyses, encompassing Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The landscape of immune cell infiltration within the tumor microenvironment was evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA). Furthermore, scRNA-seq data were leveraged to dissect cellular heterogeneity and examine the expression patterns of PSMD14 across distinct cell populations. Finally, immunohistochemical staining was applied to validate PSMD14 protein expression levels in clinical tissue samples. Results: Our findings demonstrated that PSMD14 and EIF3H were markedly upregulated in LIHC tissues, with PSMD14 emerging as a critical prognostic indicator. A risk stratification model constructed from JAMM family genes effectively categorized patients into distinct high- and low-risk cohorts, where the high-risk group displayed significantly shorter overall survival. The dysregulated expression of PSMD14 is partly attributable to copy number alterations and DNA methylation patterns, showing associations with multiple DNA methyltransferases. Functional enrichment analyses indicated that elevated PSMD14 expression is involved in metabolic pathways and oncogenic signaling cascades. Moreover, PSMD14 expression was linked to an immunosuppressive tumor microenvironment, exhibiting a positive correlation with Th2 cells and an inverse relationship with cytotoxic immune cells. scRNA-seq validated the predominant expression of PSMD14 in malignant epithelial cells. A nomogram incorporating PSMD14 expression and clinical variables was developed to predict patient survival probabilities at 1 and 5 years. Additionally, immunohistochemical analysis of 55 clinical samples revealed that PSMD14 protein levels were substantially higher in LIHC tissues compared to adjacent non-tumorous tissues. Conclusions: These results indicate that PSMD14 may serve as a promising prognostic biomarker and therapeutic target for LIHC, highlighting the need for further exploration of its underlying molecular mechanisms and therapeutic applications.