Identification and verification of biomarkers associated with integrated stress response in heart failure.

Heart failure (HF) is a global disease affecting millions worldwide. This study aimed to identify and validate HF biomarkers associated with the integrated stress response (ISR), providing novel insights into pathogenesis and potential therapeutic targets. Transcriptomic datasets were acquired from open-access repositories, and integrated stress response-related genes (ISRGs) were compiled through literature review. Candidate biomarkers were identified by overlapping ISRGs with differentially expressed genes (DEGs), followed by machine learning selection and expression validation. Functional analyses included nomogram construction, enrichment analysis, immune infiltration assessment, regulatory network building, drug prediction, tissue expression profiling, and RT-qPCR validation. PSME4 and SQSTM1 were identified as key biomarkers. The nomogram model exhibited strong predictive accuracy for HF. Enrichment analyses indicated that these genes were associated with pathways such as ribosome and viral myocarditis. Eight immune cell types, including neutrophils and follicular helper T cells, were significantly altered. Regulatory analysis revealed that the biomarkers were predicted to be modulated by miRNAs (e.g., hsa-miR-7-5p) and indirectly regulated by lncRNAs (e.g., ZFAS1). Besides, several drugs, including demecolcine and bortezomib, were predicted for therapeutic potential. Tissue-specific expression analysis confirmed differential levels, and RT-qPCR revealed reduced PSME4 and elevated SQSTM1 expression in HF patients. PSME4 and SQSTM1 were identified as ISR-related biomarkers in HF, highlighting their potential for diagnostic application and therapeutic development.