NRXN3 is a presynaptic transmembrane cell adhesion molecule that functions as a synaptic organizer in the nervous system 1. It mediates trans-synaptic signaling by binding to postsynaptic partners including cerebellins and GRID1, regulating NMDA and AMPA receptor activity at hippocampal synapses [UniProt]. NRXN3 expression extends beyond neurons to cardiac, pulmonary, pancreatic, and other tissues 2, where it participates in cell-cell adhesion and intercellular connections involving dystroglycan and extracellular matrix proteins. Genomically, NRXN3 variants associate with multiple neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and intellectual disability 1, with gene-by-environment interactions modulating smoking behavior maintenance 3. NRXN3 is also implicated in fibromyalgia pathogenesis through genome-wide association studies 4. Beyond the nervous system, NRXN3 dysfunction correlates with cardiac pathology: reduced expression associates with impaired left ventricular contractility, incident heart failure, and cardiovascular mortality in diabetic patients 5. Recent evidence reveals NRXN3 regulates pyroptotic cell death in intrahepatic cholangiocarcinoma by blocking caspase-3 phosphorylation, thereby enhancing chemosensitivity to gemcitabine 6. Additionally, NRXN3-mediated signaling participates in retinal neovascularization pathways in oxygen-induced retinopathy 7.