DARS2 (aspartyl-tRNA synthetase 2, mitochondrial) catalyzes the attachment of aspartate to tRNA(Asp) in mitochondria, essential for mitochondrial protein translation 1. Beyond this canonical aminoacylation function, DARS2 exhibits pleiotropic roles in cellular homeostasis and disease pathogenesis. DARs2 mutations cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), characterized by progressive spasticity, ataxia, and axonal degeneration 1. DARS2 variants also associate with axonal Charcot-Marie-Tooth disease, suggesting a disease spectrum ranging from isolated peripheral neuropathy to combined central-peripheral nervous system involvement 2. At the molecular level, DARS2 mutations dysregulate mRNA metabolism and splicing, impair mitochondrial function, and reduce neuronal growth 3. In cancer biology, DARS2 promotes bladder cancer progression by upregulating CDK4 and enhancing PINK1-mediated mitophagy, facilitating G1-to-S transition and suppressing senescence 4. DARS2 modulates immune responses through PD-L1-mediated immune evasion 5. Extracellularly, circulating DARS2 released during bacterial pneumonia exhibits innate immune properties and is controlled by FBXO24-mediated ubiquitylation 6. Conversely, TMAO downregulates DARS2, enhancing mitochondrial ROS production and inflammation 7. Therapeutically, AAV9-DARS2 gene supplementation rescues mitochondrial function and reduces neurodegeneration in LBSL models 1, supporting gene therapy approaches for this rare disorder.