TMEM25 is a transmembrane protein with dual roles in neuronal and cancer biology. In neurons, TMEM25 localizes to late endosomes and modulates neuronal excitability by promoting NMDA receptor NR2B subunit degradation through lysosomal acidification 1. This function is clinically relevant to epilepsy—TMEM25 expression is decreased in epileptic brain tissue, and overexpression attenuates seizure phenotypes 1. Additionally, TMEM25 promotes neural progenitor cell expansion, with human-biased expression levels facilitating cortical development through enhanced responsiveness to extracellular signals via Akt signaling 2. In cancer contexts, TMEM25 functions as a tumor suppressor. It inhibits monomeric EGFR-mediated STAT3 activation in triple-negative breast cancer (TNBC)—TMEM25 deficiency allows ligand-independent STAT3 phosphorylation, promoting TNBC progression, while TMEM25 restoration suppresses this pathway 3. TMEM25 expression is frequently reduced in multiple cancers through CpG island hypermethylation 4. Low TMEM25 expression correlates with poor prognosis in renal clear cell carcinoma and associates with increased drug resistance in breast cancer 56. Conversely, TMEM25 presence predicts favorable outcomes and extended survival in breast cancer patients 7. TMEM25 encodes both transmembrane and secreted isoforms via alternative splicing and belongs to the immunoglobulin superfamily 8.