ZFYVE28 (zinc finger FYVE-type containing 28) is a negative regulator of epidermal growth factor receptor (EGFR) signaling that operates through endosomal trafficking mechanisms. The protein contains a FYVE domain enabling phosphatidylinositol-3-phosphate binding to early endosome membranes 1. ZFYVE28 promotes EGFR degradation by inhibiting recycling endosome formation while facilitating early-to-late endosome conversion 1. mTORC1 directly phosphorylates ZFYVE28 at serine 670, promoting its monoubiquitination and stability; conversely, unphosphorylated ZFYVE28 undergoes proteasomal degradation 2. Beyond EGFR, ZFYVE28 regulates insulin receptor signaling, with increased expression correlating with insulin resistance by promoting phosphorylated insulin receptor degradation 1. In podocytes, ZFYVE28 modulates EGFR localization and expression, though it is dispensable for glomerular filtration barrier development and maintenance 3. ZFYVE28 variants have been associated with intellectual disability in consanguineous populations 4 and polycystic ovary syndrome in women with epilepsy 5. Additionally, ZFYVE28 methylation status associates with sleep duration and is vulnerable to environmental perturbations including maternal tobacco smoke exposure 67. These findings establish ZFYVE28 as a multifunctional endosomal protein controlling growth factor signaling with implications for metabolic and neurological diseases.