HAPLN4 (hyaluronan and proteoglycan link protein 4) is a perineuronal net (PNN) component essential for structural organization of extracellular matrix in the central nervous system. It mediates proper localization of brevican in brainstem and cerebellar PNNs, where it contributes to GABAergic synapse formation and transmission between Purkinje cells and deep cerebellar nuclei. HAPLN4 localizes to inhibitory synapses and serves as a structural constituent of synapse-associated extracellular matrix 1. Genetically predicted elevation of circulating HAPLN4 is associated with decreased risk of visceral obesity and may represent a safe drug target for obesity treatment 2. HAPLN4 has emerged as a candidate therapeutic target identified through proteome-wide Mendelian randomization for rheumatoid arthritis, where it is downregulated in disease 3. Additionally, HAPLN4 is implicated in schizophrenia and bipolar disorder pathophysiology based on genome-wide association evidence and DNA methylation studies 4, 5. It was identified as a genetic comorbid gene linking triglyceride-glucose index to metabolic dysfunction-associated steatotic liver disease 6. Variants in HAPLN4 are also associated with essential tremor in families with cerebellar dysfunction 7. Expression of HAPLN4 is dynamically regulated in non-alcoholic steatohepatitis by PPAR α/δ agonists 8. These findings suggest HAPLN4's role extends beyond PNN structural function to broader metabolic and psychiatric disease mechanisms.