Integrated multi-omics and single-cell analysis identify SERPINE1 as a key mediator of the inflammatory tumor microenvironment in PDAC

Background Chronic inflammation is increasingly recognized as a fundamental driver of pancreatic ductal adenocarcinoma (PDAC) initiation and progression. Although numerous bioinformatics studies have characterized genetic alterations in PDAC, the key inflammatory regulators that bridge tumor cells and the immunosuppressive stroma remain unclear. Methods We conducted an integrative multi-omics analysis of TCGA, GEO, and ArrayExpress datasets to define inflammation-associated molecular signatures in PDAC. Differentially expressed genes were analyzed through pathway enrichment, protein–protein interaction modeling, and immune infiltration profiling. Immunotherapeutic relevance was assessed using the IMvigor210 cohort and TIDE algorithm, while drug repurposing candidates were identified via molecular docking. Single-cell RNA sequencing and in vitro functional assays were employed to validate gene expression patterns and mechanistic functions within the PDAC microenvironment. Results Our multi-cohort analysis revealed a robust inflammation-associated gene network in PDAC, with SERPINE1 emerging as a consistent central hub. Elevated SERPINE1 expression was tightly linked to a profoundly immunosuppressive tumor microenvironment and predicted diminished responsiveness to immunotherapy across datasets. Structure-based molecular docking further identified Lenvatinib and Dasatinib as previously unappreciated candidate inhibitors of SERPINE1, suggesting actionable therapeutic opportunities. Single-cell transcriptomic profiling resolved nine major cellular compartments and pinpointed fibroblasts as the principal stromal niche orchestrating SERPINE1-driven crosstalk between inflammation and immune evasion, a cellular origin that has not been systematically defined before. Translational analyses demonstrated consistently elevated SERPINE1 in tumor tissues, and functional validation using CRISPR-mediated knockout in PDAC cell lines significantly impaired proliferation and migration while inducing robust apoptosis, thereby establishing SERPINE1 as a previously underappreciated but essential driver of PDAC aggressiveness. Conclusions This integrative multi-omics and single-cell analysis establishes SERPINE1 as a central orchestrator of inflammation-driven stromal remodeling and immune evasion in PDAC. Its strong prognostic power, combined with newly revealed druggability, positions SERPINE1 as a tractable therapeutic axis for precision immunotherapy and rational drug repurposing. These findings provide a mechanistically grounded and clinically actionable entry point into targeting the inflammatory tumor microenvironment of pancreatic cancer.