TMEFF1 is a neuron-specific transmembrane protein with dual roles in antiviral immunity and cancer biology. Primarily, TMEFF1 functions as a restriction factor for herpes simplex virus 1 (HSV-1) in the central nervous system 1. It blocks HSV-1 entry into cortical neurons by preventing the association between viral glycoprotein D and its cell surface receptor NECTIN1, and also inhibits interactions between viral glycoprotein B and non-muscle myosin heavy chains IIA and IIB 2. TMEFF1 is constitutively highly expressed in brain neurons but is not regulated by type I interferon, representing a distinct antiviral pathway 2. Genetic deficiency in TMEFF1 causes severe susceptibility to HSV-1 encephalitis in children, with TMEFF1-deficient mice showing increased viral replication specifically in brain neurons 12. Clinically, inherited TMEFF1 mutations underlie approximately 8-10% of childhood herpes simplex encephalitis cases, enabling new diagnostic approaches 3. Additionally, TMEFF1 may function as a tumor suppressor in brain cancers, as 96% of brain tumors showed reduced TMEFF1 expression compared to normal brain tissue, and ectopic TMEFF1 expression inhibited brain cancer cell growth 4. However, TMEFF1 expression promotes malignancy in ovarian and liver cancers through interactions with ST14, AHNAK, and TGF-β/Smad signaling pathways, suggesting tissue-specific functional differences 567.