Multiomics and Genomic Alteration Characterization Identifies VDAC1 as a Mitochondrial-Associated Biomarker in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biological behavior and limited therapeutic responsiveness. Identifying genetically and biologically interpretable biomarkers remains critical for improving molecular stratification of this malignancy. Here, we performed an integrative analysis combining bulk transcriptomics, genomic alteration profiling, immune-response modeling, and functional validation to characterize the clinical relevance of voltage-dependent anion channel 1 (VDAC1) in PDAC. Genomic analyses demonstrated that VDAC1 exhibits a low somatic mutation frequency in PDAC and that its dysregulated expression may be partly associated with copy number alterations. Transcriptomic analyses further showed that VDAC1 is significantly upregulated in tumor tissues and associated with unfavorable clinical outcomes. Multiomics characterization indicated that high VDAC1 expression is linked to mitochondrial metabolic programs and reduced cytotoxic immune signatures. Functional validation demonstrated that VDAC1 silencing impaired pancreatic cancer cell proliferation and disrupted mitochondrial homeostasis, including reduced mitochondrial membrane potential, ATP production, and mitochondrial reactive oxygen species levels. In addition, VDAC1 perturbation reduced immunosuppressive cytokine output, suggesting a tumor-intrinsic connection between mitochondrial metabolic regulation and immune-related programs. Collectively, this study provides a genomic alteration-informed multiomics framework supporting VDAC1 as a mitochondrial-associated biomarker in PDAC and highlights its potential relevance for molecular characterization of pancreatic cancer.