RETREG2 (also known as FAM134A) is an endoplasmic reticulum (ER)-anchored autophagy receptor that regulates selective ER degradation (ER-phagy). Under basal conditions, RETREG2 exists in an inactive state but becomes activated upon cellular stress and autophagy induction 1. Upon activation, RETREG2 induces ER fragmentation and mediates delivery of ER segments into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins 1. Unlike its paralogue FAM134B/RETREG1, RETREG2 maintains ER morphology and executes collagen quality control through a LIR (LC3-interacting region)-independent mechanism 1. RETREG2 also contributes to mitotic cell rounding; its depletion impairs mitotic progression by affecting metaphase plate alignment and reducing pressure generation through myosin II relocalization 2. Genetically, RETREG2 is a novel glioma susceptibility gene, with increased expression associated with elevated glioma risk across multiple subtypes 3. Additionally, cancer-secreted microRNAs can suppress RETREG2 expression to promote osteoblastic phenotype induction in bone metastatic microenvironments 4, suggesting RETREG2's broader role in cellular homeostasis and disease pathology.