Development of a Mitochondrial Permeability Transition-Driven Necrosis-Related Prognostic Signature in Cervical Cancer: Integrating Bulk Transcriptomic and Single-Cell Data.

Background: Cervical cancer (CC) is a prevalent gynecological malignancy with notable heterogeneity. The role of mitochondrial permeability transition (MPT)-driven necrosis, a form of cell death due to mitochondrial dysfunction, in CC progression and prognosis is poorly understood and represents a promising therapeutic target for cancers. This study aimed to create a new prognostic signature linked to MPT-driven necrosis, improving CC prediction and prognosis.

Methods: This study utilized the GSE63514, TCGA-CESC, CGCI-HTMCP-CC, and GSE197641 transcriptome datasets. Firstly, the GSE63514 dataset was utilized to identify differentially expressed genes (DEGs). Differentially expressed MPT-driven necrosis-related genes (DE-MRGs) were obtained by intersecting DEGs with MRGs. Regression analyses were performed to identify genes significantly associated with prognosis. A prognostic model was established in TCGA-CESC, followed by independent validation and nomogram construction. Additional analyses included immune infiltration, enrichment analysis, and drug susceptibility based on high- and low-risk groups. Finally, cell communication analysis was performed to investigate interactions between key cell types.

Results: A total of 156 DE-MRGs were identified. Regression analyses identified three prognostic genes (ICOS, MMP3, and POSTN) to construct a prognostic risk signature. Then, risk score was an independent prognostic factor for CC, and a nomogram demonstrated effective predictive accuracy for CC survival outcomes. The risk signature was linked to immune-associated processes such "Antigen processing and presentation" and immune cell infiltration, especially M0 macrophages and CD8 T cells. Cell communication analysis uncovered a strong interaction between endothelial cells and monocytes. To validate the molecular mechanisms, qRT-PCR, cell proliferation, and wound healing assays were performed. Functional tests showed that MMP3 and POSTN knockdown drastically reduced CC cell growth and migration.

Conclusion: This study developed a novel prognostic risk signature based on ICOS, MMP3, and POSTN. MMP3 and POSTN knockdown significantly decrease CC cell growth and migration, highlighting their potential as therapeutic targets.