Multi-Omics Insights into the Impact of MDH2 on Breast Cancer Progression: A Promising Druggable Target.

OBJECTIVES: Breast cancer is characterized by significant metabolic dysregulation, in which altered enzyme activity plays a central role. Malate dehydrogenase 2 (MDH2), a key enzyme in the tricarboxylic acid cycle, has been implicated in several malignancies, but its role in breast cancer tumorigenesis and progression remains unclear. We aimed to elucidate the oncogenic role of MDH2 in breast cancer and to evaluate its potential as a diagnostic, therapeutic, and prognostic biomarker. METHODS: We combined in vitro cell-based assays with mouse xenograft models to systematically dissect how MDH2 governs breast cancer growth. In vitro, we assessed the effects of altered MDH2 expression on proliferation, migration, epithelial-mesenchymal transition (EMT), glucose consumption, and adenosine-5(')-triphosphate (ATP) production. In vivo, we dynamically monitored tumor growth driven by MDH2 overexpression. Transcriptomic profiling, untargeted metabolomics, and in-silico druggability analyses were integrated to elucidate downstream mechanisms and therapeutic potential. RESULTS: In vitro, MDH2 depletion suppressed breast cancer cell proliferation and migration, reversed EMT, and markedly reduced glucose consumption and ATP production. In vivo, MDH2 overexpression accelerated xenograft tumor growth. Transcriptomic profiling revealed MDH2 had modified the gene expression profile of breast cancer cells, affecting several metastasis-related genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, also known as AKT) pathway as a downstream effector pathway of MDH2. Untargeted metabolomics uncovered 62 MDH2-regulated metabolites, including the immunomodulatory metabolites adenosine and linoleic acid. In-silico modeling confirmed MDH2 as a novel druggable target. CONCLUSION: Our findings highlight the role of MDH2 in breast cancer metabolism and suggest it as a promising target for cancer therapies targeting metabolism and tumor growth.