UGGT2 (UDP-glucose glycoprotein glucosyltransferase 2) functions as a quality control sensor in the endoplasmic reticulum, recognizing misfolded glycoproteins and reglucosylating their N-linked glycans to flag them for retention and potential refolding 1. Like its paralog UGGT1, UGGT2 exhibits glucosyltransferase activity with similar glycan specificity and preferential recognition of proteins with non-native conformations 1. However, quantitative glycoproteomics reveals distinct substrate preferences: while UGGT1 dominantly targets large plasma membrane proteins, UGGT2 favors smaller, soluble lysosomal proteins among the 71 identified UGGT substrates 2. The enzyme forms heterodimeric complexes with Sep15, which markedly enhances its glucosyltransferase activity 1. UGGT2's clinical significance extends beyond protein folding quality control, as genetic variants have been associated with doxorubicin-induced cardiotoxicity through Mendelian randomization analyses 3 and potentially with antihypertensive drug response 4. Additionally, UGGT2 variants have been identified as potential autosomal recessive candidates in early-onset colorectal cancer cases 5. The therapeutic modulation of UGGT2, alongside UGGT1, represents a promising approach for rescuing secretion of disease-associated misfolded glycoproteins 6.