MDH2 (malate dehydrogenase 2) is a mitochondrial enzyme catalyzing NAD+-dependent malate oxidation, functioning as a central hub in the tricarboxylic acid (TCA) cycle and malate-aspartate shuttle 12. MDH2 activity is dynamically regulated by post-translational modifications: palmitoylation by ZDHHC18 enhances activity and mitochondrial respiration 2, while lactylation impairs mitochondrial function 3, and deacetylation by Sirt3 reduces activity 1. Deubiquitination by USP5 increases MDH2 stability 4. Clinically, MDH2 dysregulation contributes to multiple pathologies. In myocardial ischemia-reperfusion injury, MDH2 lactylation induces ferroptosis; dexmedetomidine ameliorates injury by reducing lactylation 3. Decreased MDH2 activity impairs TCA cycle flux, causing fibroblast-like synoviocyte senescence and osteoarthritis progression 1. In cancer, elevated MDH2 activity supports oxidative phosphorylation in ovarian cancer 2 and glioblastoma stem cells, with the latter involving epitranscriptomic remodeling via α-ketoglutarate and m6A methylation 5. Conversely, MDH2 inhibition by glibenclamide delays aging through metabolic-epigenetic regulation 6. MDH2 also interacts with fructose-1,6-bisphosphate, functioning in glucose signaling 7, and is present on large extracellular vesicles 8.