<p>Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options. This study aimed to explore the role of disulfidptosis‑related genes (DRGs) in shaping the tumor immune microenvironment of PDAC, and to identify candidate prognostic biomarkers with potential therapeutic implications. DRG expression was profiled using transcriptomic data from The Cancer Genome Atlas (TCGA), and consensus clustering identified two molecular subtypes—C1 and C2—with C2 exhibiting a higher disulfidptosis activity score and distinct immune‑related features. Univariate and multivariate Cox regression analyses identified MYH9 as an independent prognostic factor. A nomogram incorporating MYH9 expression, age, gender, AJCC pathological stage, and histological grade predicted 1‑, 2‑, and 3‑year overall survival with areas under the curve (AUC) values of 0.66, 0.80, and 0.64, respectively. Further immune and drug‑sensitivity analyses revealed that MYH9 expression correlated significantly with immune cell infiltration and response to agents such as staurosporine, dasatinib, and oxaliplatin. Experimental validation showed that MYH9 overexpression significantly promoted the proliferation of PDAC cells, whereas MYH9 knockdown markedly suppressed it, and rescue experiments with the MYH9 inhibitor blebbistatin further confirmed its regulatory role in PDAC cell growth. Moreover, clinical specimen validation confirmed that elevated MYH9 expression correlated with reduced CD8⁺ T cell infiltration and poorer overall survival in PDAC patients. Collectively, these findings indicate that DRG expression profiles are closely associated with the PDAC tumor microenvironment. MYH9, identified from the disulfidptosis‑related gene set, serves as a reliable prognostic biomarker and a candidate oncogene in PDAC. Its potential association with disulfidptosis provides a preliminary basis for further mechanistic investigation and the exploration of targeted therapy for PDAC.</p>