Identification of mitochondrial-related subtypes and development of a prognostic model for pancreatic ductal adenocarcinoma.

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a poor prognosis. Mitochondrial dysfunction, including alterations in metabolism, dynamics, and DNA, is increasingly recognized as a critical factor in the initiation and progression of pancreatic cancer. This study aimed to systematically investigate the role of mitochondrial dysfunction in PDAC to identify mitochondria-related genes (MitoRGs) of prognostic significance, explore associated molecular subtypes, and examine their effects on the tumor immune microenvironment.

METHODSWe integrated transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify a set of MitoRGs with significant prognostic value for PDAC. Their expression was further validated in PDAC cells and using single-cell RNA-sequencing data. Unsupervised clustering was employed to classify PDAC patients into distinct subtypes based on MitoRG expression patterns. A robust prognostic model was subsequently constructed using least absolute shrinkage and selection operator-Cox regression analysis. The predictive accuracy of the model for 1-, 3-, and 5-year overall survival (OS) was assessed. The immune cell infiltration and genomic features of the risk groups defined by the model were also analyzed. Finally, a clinically applicable nomogram was developed to facilitate prognostic prediction.

RESULTSBased on MitoRG expression, PDAC patients were classified into two distinct subtypes (clusters A and B). Patients in cluster A exhibited significantly better OS than those in cluster B. A prognostic model based on a seven-MitoRG signature was established, which demonstrated high predictive accuracy. The high-risk group, as defined by the model, was characterized by an immunosuppressive tumor microenvironment, featuring reduced cytotoxic T-cell activity and increased stromal components. This group also showed significant enrichment of driver mutations such as KRAS and TP53.

CONCLUSIONSThis study established a significant link between mitochondrial dysfunction and PDAC molecular subtypes, immune microenvironment remodeling, and clinical prognosis. The developed seven-MitoRG signature and nomogram could serve as reliable prognostic tools. These findings provide insights into the role of mitochondria in the pathogenesis of PDAC and offer potential targets for developing personalized therapeutic strategies.