HEXB encodes the beta subunit of hexosaminidase, a lysosomal enzyme essential for degrading glycoconjugates and gangliosides. The enzyme hydrolyzes N-acetyl-D-hexosamine residues from oligosaccharides, neutral glycolipids, and mucopolysaccharides 12. Critically, only the hexosaminidase A isozyme (containing HEXB) efficiently degrades GM2 gangliosides in the presence of GM2 activator protein 23. HEXB plays a vital role in microglia-neuron homeostasis: microglia deliver HEXB to neurons for GM2 degradation, and HEXB deficiency causes pathological GM2 accumulation triggering neurodegeneration in Sandhoff disease 4. HEXB mutations cause GM2-gangliosidosis type 2 (Sandhoff disease), characterized by progressive neurological deterioration; disease pathogenesis involves cGAS-STING-mediated innate immune activation triggered by lysosomal dysfunction 5. Beyond lysosomal storage disease, HEXB is implicated in cancer metabolism, where it promotes glycolysis in glioblastoma through HIF1α stabilization and facilitates extracellular vesicle release in hepatocellular carcinoma 67. AAV gene therapy targeting HEXB has shown early safety and proof-of-concept efficacy in Tay-Sachs patients 8. HEXB serves as a robust microglia-specific marker for CNS research 9.