CDS2 Drives Tumor Progression in Epithelial Ovarian Cancer via the PI3K/AKT Pathway.

Abstract

Background: Epithelial ovarian cancer (EOC) frequently disseminates within the lipid-rich peritoneal cavity, where tumor progression is accompanied by metabolic adaptations involving lipid utilization and mitochondrial function. Although these metabolic alterations are increasingly recognized as important features of EOC progression and peritoneal metastasis, the molecular factors linking mitochondrial-lipid metabolic remodeling with aggressive tumor behavior remain incompletely characterized. We therefore integrated mitochondrial- and lipid metabolism-related transcriptomic analyses to identify candidate regulators and further investigated the clinical and biological features associated with CDS2.

Results: Seven key genes associated with mitochondrial and lipid metabolism were identified in EOC through comprehensive bioinformatic analyses and were used to construct the MALRS prognostic model. Further integration of FIGO stage, histologic grade, and MALRS scores yielded a nomogram whose calibration plots showed good agreement between predicted and observed 1-, 3-, and 5-year survival probabilities. Subsequent screening of these candidate genes in chemotherapy-resistant datasets identified CDP-diacylglycerol synthase 2 (CDS2) as the most consistently upregulated candidate gene. Clinical validation confirmed that CDS2 was significantly overexpressed in tumor tissues and was associated with advanced disease stage, and survival analysis showed that higher CDS2 expression was associated with shorter progression-free survival (PFS) in stage III/IV patients. Functional characterization demonstrated that CDS2 overexpression promoted both lipid droplet accumulation and migratory capacity in ovarian cancer cells. Pathway analysis identified significant enrichment of PI3K/AKT signaling, and experimental validation confirmed CDS2-mediated hyperactivation of PI3K/AKT phosphorylation. Computational immune-deconvolution analyses further identified exploratory associations between CDS2 expression, estimated T-cell abundance, and immune-checkpoint transcripts.

Conclusion: CDS2 is a lipid metabolism-associated candidate biomarker linked to aggressive clinicopathological features in EOC. Our findings associate CDS2 with disease progression, PI3K/AKT-related signaling, and immune-related transcriptomic features, supporting its further evaluation as a candidate prognostic marker.