LGI3 (leucine rich repeat LGI family member 3) functions as a secreted regulatory protein with diverse roles in neuronal exocytosis, keratinocyte biology, and cellular signaling. In the nervous system, LGI3 associates with syntaxin 1, a key SNARE component, and attenuates calcium-evoked glutamate release from synaptosomes, suggesting it negatively regulates neuronal exocytosis 1. The protein is predominantly expressed in brain tissue with developmentally regulated patterns 2. In skin biology, LGI3 acts as a keratinocyte-derived cytokine that promotes cell differentiation via Akt pathway activation and enhances keratinocyte migration in high-glucose environments through β-catenin accumulation 34. LGI3 also stimulates melanogenesis and shows reduced expression in vitiligo patients 5. The protein responds to inflammatory stimuli, being secreted by keratinocytes following LPS exposure through TRIF-dependent NF-κB signaling and binding to ADAM22 receptor 6. In cancer contexts, LGI3 exhibits tumor-suppressive properties in pancreatic adenocarcinoma but promotes progression in TFE3-rearranged renal cell carcinoma through GEMIN6/AURKB signaling 78. These findings establish LGI3 as a multifunctional secreted protein important for neuronal regulation, skin homeostasis, and disease pathogenesis.