ME2 (malic enzyme 2) is a NAD-dependent mitochondrial enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate, playing a central role in metabolic regulation and mitochondrial function 1. ME2 exists in multiple cellular compartments with distinct functions: mitochondrial ME2 regulates the tricarboxylic acid (TCA) cycle and supports oxidative respiration 2, while cytoplasmic ME2 can function as a metabolic scaffold for glycolytic enzymes 2. ME2 activity is regulated through post-translational modifications, including desuccinylation by SIRT5 1, acetylation by ACAT1 3, and methylation by PRMT1 4. Beyond energy metabolism, fumarate binding to ME2 promotes mitochondrial biogenesis by facilitating dimer formation that activates nucleotide synthesis and mitoribosome assembly 5. In immune cells, ME2 is essential for CD8+ T cell activation and anti-tumor immunity through TCA cycle regulation 6. Clinically, ME2 dysregulation is implicated in multiple cancers (colorectal, ovarian, hepatocellular) where upregulation promotes mitochondrial respiration and chemoresistance 134, and genetic variants in ME2 are associated with genetic generalized epilepsy susceptibility 7.