EDEM3 is an ER-localized α-1,2-mannosidase that plays a crucial role in endoplasmic reticulum-associated degradation (ERAD) by facilitating the disposal of misfolded glycoproteins 1. The protein catalyzes mannose trimming from M8B oligosaccharides to produce M7, M6, and M5 structures, creating determinant signals that target glycoproteins for proteasomal degradation 1. EDEM3 consists of four functional domains (GH47, intermediate, protease-associated, and intrinsically disordered) that cooperatively regulate substrate binding, folding, and protein turnover timing 2. Beyond ERAD, EDEM3 maintains ER homeostasis by attenuating the unfolded protein response and exhibits pro-survival functions 34. Clinically, EDEM3 overexpression is associated with multiple cancers including prostate, ovarian, and hepatocellular carcinoma, correlating with poor prognosis and therapy resistance 453. In cancer contexts, EDEM3 promotes radioresistance in prostate cancer 4, facilitates M2-like macrophage polarization contributing to immunotherapy resistance 6, and supports viral replication in hepatitis B infection 3. The protein's cytoprotective role against ER stress makes it a potential therapeutic target for sensitizing tumors to treatment.