Abstract
BACKGROUND: PERK (Protein kinase R-like endoplasmic reticulum kinase), encoded by EIF2AK3, is a key ER stress sensor that regulates protein synthesis and the unfolded protein response (UPR). Its dysregulation is linked to cancer development and progression. This study investigated EIF2AK3/PERK expression across 28 tumour types (n = 7,251) and their matched normal adjacent tissues (NATs; n = 667) from the Cancer Genome Atlas (TCGA) database, along with additional normal tissue samples from the Genotype-Tissue Expression (GTEx) project (n = 1,736), and 1,179 tumour cell lines, examining correlations with patient demographics, tumour stage, survival and genetic alterations. RESULTS: Transcriptomic analysis revealed EIF2AK3 upregulation in multiple cancers, with proteomic data supporting increased PERK protein levels in specific tumour types. EIF2AK3 expression was correlated with age, gender, tumour stage and survival endpoints in a context-dependent manner. Mutational analysis identified frequent EIF2AK3 alterations, including missense, gain and amplification events. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the cell cycle, proteoglycans in cancer and focal adhesion pathways were among the most consistently enriched across tumour types, particularly in tumours with high EIF2AK3 expression. These tumours also showed enrichment in Rap1 signalling, PI3K-Akt signalling, cytoskeletal regulation, ubiquitin-mediated proteolysis and nucleocytoplasmic transport, indicating a stress-adaptive invasive phenotype. In contrast, tumours with low EIF2AK3 expression demonstrated enrichment in focal adhesion, AGE-RAGE signalling and cytoskeletal organisation, suggesting a tumour state dependent on adhesion integrity and extracellular matrix (ECM) interaction rather than stress-induced plasticity. Gene Ontology (GO) enrichment analysis supported these observations, with high EIF2AK3 tumours displaying strong associations with cell adhesion, ECM structural remodelling and actin binding, while low EIF2AK3 tumours showed enrichment in cytoskeletal stability and axonogenesis. Hierarchical clustering revealed a distinct gene cluster associated with EIF2AK3 across several tumour types. Protein-protein interaction (PPI) and enrichment analyses linked this cluster to tumour progression and cell adhesion. CONCLUSION: These findings underscore the central role of EIF2AK3/PERK in regulating cancer-associated pathways. Its expression stratifies tumours into biologically distinct phenotypes, with one favouring ER stress adaptation and invasiveness, and the other reliant on ECM organisation and adhesion homeostasis. EIF2AK3 may thus serve as a potential therapeutic target in multiple cancers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-026-04910-8.