Molecular characterization of ovarian mesonephric-like adenocarcinoma: Insights from single-cell RNA sequencing and mitochondrial metabolism.

Objectives: Ovarian mesonephric-like adenocarcinoma (MLA) is a rare malignancy with limited understanding of its molecular features and therapeutic vulnerabilities. Although similar to uterine MLA, its unique characteristics remain undefined. This study aimed to characterize ovarian MLA using single-cell RNA sequencing (scRNA-seq) and compare it with high-grade serous ovarian cancer (HGSOC). Methods: We analyzed the cellular and molecular heterogeneity of an ovarian MLA sample using scRNA-seq. Differential gene expression and pathway analyses were performed to identify unique molecular signatures and therapeutic targets. HGSOC scRNA-seq datasets were used for comparative analysis. Results: Ovarian MLA demonstrated reduced heterogeneity, with a predominance of epithelial cells compared to HGSOC. Transcriptomic profiling revealed an upregulation of mitochondrial metabolism and lipid biosynthesis genes, indicating a metabolic shift toward oxidative phosphorylation. Gene enrichment and protein-protein interaction analyses identified distinct pathways, including mitochondrial biogenesis and dynamics, suggesting mitochondrial reprogramming. Conclusions: This study provides the first scRNA-seq-based molecular characterization of ovarian MLA, differentiating it from HGSOC. Findings suggest potential therapeutic avenues, with a proposed combination therapy targeting MAP kinase and PI3K/AKT/mTOR pathways. Validation in larger cohorts is necessary for clinical application.