NEGR1 (neuronal growth regulator 1) is an IgLON family cell adhesion molecule critical for neuronal function and brain health. As a membrane-anchored protein with immunoglobulin domains, NEGR1 mediates homo- and heterophilic cell-cell adhesion interactions and undergoes metalloprotease-mediated shedding to generate soluble factors 1. NEGR1 regulates synaptic plasticity, dendritic spine density, and myelination-related signaling pathways 2. The gene shows robust genetic associations with depression and obesity, with genome-wide significance in both conditions 3. Mechanistically, NEGR1 modulates monoaminergic neurotransmission, particularly dopamine and serotonin systems; Negr1-deficient mice exhibit altered dopamine release, elevated monoamine levels, and enhanced antidepressant drug responsiveness 4. Elevated NEGR1 expression in ventral hippocampus and medial prefrontal cortex drives anxiety- and depression-like behaviors through synaptic dysfunction and dendritic spine loss 2. NEGR1 acts as a causal gene for depression, identified through proteome-transcriptome integration approaches 5. Beyond neuropsychiatric disorders, reduced NEGR1 promotes colorectal cancer liver metastasis via PI3K/AKT pathway activation and M2 macrophage polarization 6. NEGR1 also links late-onset depression to Alzheimer's disease pathology through ADAM10-mediated shedding, enhancing neuroprotection against amyloid-β accumulation 7.