STEAP4 drives immune dysregulation in myocardial infarction-NSCLC comorbidity.

INTRODUCTION

Myocardial infarction (MI) and non-small cell lung cancer (NSCLC) are leading causes of morbidity and mortality worldwide, with increasing evidence pointing to a complex comorbidity between them. However, the immunological mechanisms linking these two diseases remain largely unexplored.

METHODS

We integrated bioinformatics analysis with in vivo experimental validation. MI datasets (GSE48060, GSE83500) and an NSCLC dataset (GSE19188) were obtained from the GEO database. A multilayer screening framework combining differential expression analysis, WGCNA, and machine learning algorithms (SVM-RFE, LASSO, and random forest) was applied to identify shared hub genes. A mouse model of MI and NSCLC comorbidity was established, and STEAP4 was functionally evaluated through gene knockout and siRNA mediated knockdown, with assessment of cardiac function, tumor burden, immune cell infiltration, and inflammatory cytokine levels.

RESULTS

Four hub genes, STEAP4, HP, TREM1, and CCR2, were identified, and their combined signature achieved excellent diagnostic performance (AUC = 0.987). In the comorbidity mouse model, STEAP4 was significantly upregulated in both cardiac and pulmonary tissues, correlating with elevated serum IL-6 and TNF-α levels. Immune profiling revealed increased neutrophil infiltration and reduced CD8+ T cells in the local microenvironment. Notably, STEAP4 knockout or knockdown significantly improved cardiac function, reduced myocardial fibrosis, suppressed tumor growth, and partially restored immune homeostasis.

DISCUSSION: These findings establish STEAP4 as a pivotal mediator of MI and NSCLC comorbidity, linking systemic inflammation with immune microenvironment dysregulation. Our multi-omics and functional validation approach provides a mechanistic framework for understanding cardiovascular-oncological comorbidity and positions STEAP4 as a potential diagnostic biomarker and therapeutic target for further investigation.