PIANP (PILR alpha associated neural protein) is a type-I transmembrane protein primarily localized to the basolateral plasma membrane of epithelial and neural cells 1. As a ligand for the immune inhibitory receptor PILRA, PIANP functions in immune regulation within neural tissues 2. Mechanistically, PIANP undergoes complex post-translational processing involving O-glycosylation, sialidation, and sequential proteolytic cleavage 3. Furin-like proprotein convertases process PIANP early during maturation, followed by ectodomain shedding via matrix metalloproteinases and ADAM10/17, generating C-terminal fragments further processed by γ-secretase 4. This processing is requisite for PILRA receptor-ligand interactions. Additionally, PIANP associates with APP and GABA-B receptors via sushi-domain binding, influencing presynaptic trafficking and reducing APP proteolysis to amyloid-beta 2. Functionally, PIANP enhances epithelial barrier integrity by increasing transepithelial electrical resistance and stabilizing intercellular junctions through attenuation of E-Cadherin γ-secretase-mediated cleavage 1. PIANP also participates in host-microbiome interactions and immune regulation, with predicted involvement in microbiota modulation 5. Clinically, PIANP variants are associated with intellectual disability and disorders of sex development 67, suggesting its broader relevance in neurological development and endocrine function.