MDH1 (malate dehydrogenase 1) is a cytosolic NAD(H)-dependent enzyme that catalyzes the reduction of aromatic alpha-keto acids and plays essential roles in the malate-aspartate shuttle and tricarboxylic acid cycle 123. The enzyme also catalyzes the reduction of 2-oxoglutarate to 2-hydroxyglutarate, potentially elevating reactive oxygen species 4. MDH1 has emerged as a critical regulator in acute liver failure (ALF) pathophysiology. Post-translational deacetylation of MDH1 at K118 reduces its enzymatic activity and promotes neutrophil extracellular trap formation (NETosis), a novel cell death mechanism that drives ALF progression 56. This process involves activation of the cGAS-STING inflammatory pathway, with NET-derived DNA accumulation amplifying hepatocellular injury 7. Beyond ALF, MDH1 dysregulation associates with multiple pathologies. Elevated MDH1 expression correlates with poor cancer prognosis across malignancies and influences the tumor immune microenvironment by affecting macrophage biology 8. In neurodegenerative diseases, altered MDH1 plasma levels serve as a biomarker for Alzheimer's disease pathology and microglial activation states in frontotemporal dementia 910. MDH1 mutations have been linked to developmental and epileptic encephalopathy, though comprehensive functional characterization remains incomplete 11.