ZFAND2B (also known as AIRAPL) is a zinc finger protein that plays a critical role in protein homeostasis at the endoplasmic reticulum (ER). Its primary function involves regulating the translocation and ubiquitin-mediated proteasomal degradation of nascent proteins. ZFAND2B forms a complex with p97/VCP and associated factors on the ER membrane to regulate signal-peptide-dependent translocation of secreted proteins 1. When translocation fails, ZFAND2B participates in preemptive quality control (pQC), directing mislocalized proteins bearing signal sequences toward proteasomal degradation via the p97-ZFAND2B complex 2. A key regulatory function involves controlling steady-state IGF1R receptor levels at the ER; ZFAND2B promotes ubiquitination and proteasomal degradation of newly synthesized IGF1R, thereby suppressing insulin-like growth factor signaling 3. Disease relevance is substantial: ZFAND2B loss causes myeloproliferative neoplastic transformation in mice through IGF1R pathway dysregulation, and ZFAND2B expression is widely reduced in human myeloproliferative disorders 3. Additionally, ZFAND2B overexpression protects against amyloid-beta toxicity in Alzheimer's disease models, supporting its neuroprotective role 4. These findings establish ZFAND2B as a tumor suppressor and proteostasis regulator with therapeutic implications for hematologic malignancies and neurodegenerative diseases.