ERVW-1 encodes syncytin-1, an envelope protein derived from human endogenous retroviruses that mediates cell-cell fusion through membrane fusion mechanisms involving heptad repeat coiled-coil structures [UniProt]. Beyond its canonical fusion function, ERVW-1 plays critical roles in placental development and trophoblast biology. ERVW-1 knockdown in trophoblast stem cells significantly reduces cell proliferation, differentiation, and fusion capacity, while also increasing Type I interferon receptor expression 1. Lower ERVW-1 expression in low birth weight placentas correlates with impaired placental angiogenesis and elevated hypoxia markers (HIF-1, VEGF, FLT-1), suggesting ERVW-1 supports normal vascular development 2. ERVW-1 dysregulation associates with multiple disease pathophysiologies. In schizophrenia, elevated ERVW-1 triggers ferroptosis by degrading GPX4 and SLC3A2, reducing cellular glutathione and promoting iron accumulation and neuronal death 3. ERVW-1 also activates endoplasmic reticulum stress through ATF6-mediated unfolded protein response by suppressing GANAB expression 4. Rare missense variants in ERVW-1 show genetic association with systemic lupus erythematosus, with mutant forms losing cAMP-responsive upregulation 5. In astrocytoma cells, mechanical injury and PMA stimulation downregulate ERVW-1 through FURIN-mediated pathways, affecting syncytin-1 receptor expression 6. These findings reveal ERVW-1 as a multifunctional protein regulating placental development, angiogenesis, and neurological homeostasis.