BORCS5 (BLOC-1 related complex subunit 5) is a core structural component of the hetero-octameric BORC complex, which regulates lysosomal positioning and transport 1. As part of BORC, BORCS5 associates with the cytosolic face of lysosomes and mediates recruitment of the small GTPase ARL8, coupling lysosomes to kinesin-1 motors for anterograde microtubule-dependent transport toward the cell periphery 2. This positioning is critical for cell motility and autophagy regulation, as demonstrated by BORC's role in suppressing lysosomal delivery to pathogen-containing phagosomes 3. BORCS5 loss-of-function variants cause severe neurological disease, including prenatally lethal arthrogryposis multiplex congenita with neuroaxonal dystrophy 24. Missense variants present with microcephaly, developmental epileptic encephalopathy, and progressive neurodegeneration with hypomyelination 2. Both variant types impair lysosomal proteolysis and hydrolase activity, indicating BORCS5's novel role in regulating lysosomal function beyond transport 2. Genome-wide association studies identify BORCS5 as a genetic susceptibility locus for acute respiratory distress syndrome, with expression dynamically downregulated during disease development 5. Additionally, BORCS5 dysfunction occurs in cancer pathogenesis through fusion oncogenes, where disruption of BORCS5 promotes tumor progression 67.