Open Access

ARTICLE

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

Botao Pan¹, Zirun Luo², Xiujuan Yang¹, Qingqing Liu³, Zhimin Yang^4,*, Chenglai Xia^1,3,*

1 Scientific Research Center, The Affiliated Foshan Women and Children Hospital, Guangdong Medical University, Foshan, 528000, China
2 Department of Breast, Thyroid and Head-Neck Surgery, Third Xiangya Hospital of Central South University, Changsha, 410000, China
3 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 515150, China
4 Jiangsu Natural Active Pharmaceutical Ingredient Design and Separation Technology Engineering Research Center, School of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College, Huai’an, 223003, China

* Corresponding Authors: Zhimin Yang. Email: ; Chenglai Xia. Email:

Oncology Research 2025, 33(11), 3557-3582. https://doi.org/10.32604/or.2025.068119

Received 21 May 2025; Accepted 18 August 2025; Issue published 22 October 2025

Abstract

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.

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Supplementary Material

Supplementary Material File

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