MMP9 in macrophages: A pivotal biomarker associated with immune dysregulation in interstitial cystitis/bladder pain syndrome

BACKGROUND: Studies suggest that immune abnormalities play a significant role in the pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS), yet reliable targets and biomarkers for immune intervention remain unidentified. The aim of this study was to explore the immune key targets and biomarkers that are crucial in IC/BPS. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data were integrated to analyze the immune microenvironment in IC/BPS. scRNA-seq data (GSE164557) were processed with the Seurat package, while bulk RNA-seq data (GSE11783, GSE11839, GSE28242, GSE57560) were batch-corrected using limma. Differential expression analysis was performed with limma, and immune cell infiltration was assessed through CIBERSORT. A binary classification machine learning model was built using 14 algorithms to identify key genes. Functional enrichment and gene regulatory networks were analyzed using GSEA, ORA, and pySCENIC. RESULTS: Our findings revealed substantial dysregulation of immune cell homeostasis in IC/BPS patients, characterized by aberrant macrophage polarization and T cell subset dysregulation. MMP9 has been identified as a key gene that is highly expressed in IC/BPS, particularly in macrophages. Functional annotation showed that MMP9 expression is positively correlated with the enrichment of immune pathways such as leukocyte activation and phagocytosis, and single-cell analysis demonstrated enhanced phagocytic activity in MMP9+ macrophages. Additionally, potential MMP9-targeting drugs, including teriflunomide, captopril, minocycline, and ilomastat, were identified through CMap database screening and molecular docking. CONCLUSION: This study highlights MMP9 as a key macrophage biomarker in IC/BPS, where its elevated expression is closely linked to enhanced phagocytic activity and the activation of immune-related signaling pathways.