Myeloperoxidase inhibits prostate cancer progression, suppresses the PI3K/AKT signaling pathway and reshapes the immune microenvironment.

BACKGROUND: The progression of prostate cancer (PCa) is closely associated with metabolic reprogramming and immune microenvironment dysregulation, while the mechanisms by which lactate-associated genes (LAGs) play a role remain unclear. This study aimed to elucidate the prognostic value and functional role of myeloperoxidase (MPO) in PCa and to explore its potential as a therapeutic target through comprehensive bioinformatics and experimental analyses. METHODS: We integrated The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify differentially expressed LAGs. Experimental validation using PCa tissues, PCa cell lines, and xenograft models assessed the functional role of MPO. Immune microenvironment analysis evaluated immune cell infiltration and checkpoint gene expression. Drug sensitivity predictions and Tumor Immune Dysfunction and Exclusion (TIDE) scoring were performed. Pan-cancer analysis examined MPO expression and prognostic significance across multiple cancer types. RESULTS: We identified 17 differentially expressed LAGs, finding MPO to be an independent prognostic marker for PCa. MPO was significantly downregulated in PCa tissues and PCa cell lines. Overexpression of MPO inhibited tumor proliferation in vitro and in vivo by suppressing PI3K/AKT pathway phosphorylation (p-PI3K/p-AKT) and reduced tumor volume in xenografts. The MPO high-expression group showed increased infiltration of natural killer (NK) cells and elevated expression of immune checkpoint genes. Drug sensitivity predictions indicated patients with high MPO expression were more sensitive to PI3K/AKT inhibitors (e.g., temsirolimus), but their TIDE score suggested a potentially lower response to immunotherapy. Pan-cancer analysis confirmed low MPO expression in 20 cancer types and significant associations with prognosis in cancers including colorectal cancer and glioblastoma. CONCLUSIONS: This study revealed that MPO suppresses PCa progression through dual regulation of metabolism and immunity. MPO serves as an independent prognostic marker and its downregulation contributes to tumor growth via PI3K/AKT signaling while influencing the immune microenvironment. These findings suggest MPO as a new target for combined therapeutic strategies based on metabolic intervention.