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.

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.

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.

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.

Novel drug delivery systems have been designed to enhance local drug concentrations while reducing side effects conducive to improved breast cancer treatment outcomes. This study aimed to identify the anti-cancer function of zeolite imidazole ester-based material loaded with camptothecin nanoparticles.

We utilized a zeolitic imidazolate backbone material to fabricate 9-hydroxycamptothecin nanoparticles and investigated their impact on breast cancer cell proliferation. Scanning electron microscopy and Fourier-transform infrared spectroscopy revealed changes in the carrier skeleton of the loaded 9-hydroxyl camptothecin, characterized by a reduction in surface smoothness, accompanied by slight collapses and folds on the particle surface. Notably, we detected vibration of the benzene ring in the 9-hydroxycamptothecin structure within the nanoparticles. Cell proliferation was tested by CCK-8. Protein expression was measured by Western blot. The efficacy of nanoparticles was evaluated by animal experiments.

In this study, we utilized a zeolitic imidazolate backbone material to fabricate 9-hydroxycamptothecin (9-HCPT) nanoparticles and investigated their impact on breast cancer cell proliferation. Scanning electron microscopy and Fourier-transform infrared spectroscopy revealed changes in the carrier skeleton of the loaded 9-hydroxyl camptothecin, characterized by a reduction in surface smoothness, accompanied by slight collapses and folds on the particle surface. Notably, we detected vibration of the benzene ring in the 9-HCPT structure within the nanoparticles. Using the CCK-8 method, we evaluated the inhibitory effect of these nanoparticles on breast cancer cells and observed a significant reduction in the cytotoxicity of camptothecin (CPT) when incorporated into the zeolite imidazole ester skeleton material. Immunoblot analysis showed upregulation of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and NF-κB-p65 in response to the nanoparticles. These results showed that our nanoparticles might be a useful drug delivery strategy to overcome breast cancer drug resistance.

The findings of this study suggest that nanoparticles loaded with CPT and formed from zeolite imidazole ester backbone material possess immune-enhancing properties that could suppress breast cancer progression. Accordingly, these nanoparticles hold promise as potential lead compounds for combined immunotherapy in breast cancer treatment.