UBOX5 encodes a U-box domain-containing ubiquitin ligase that functions as an E3 ubiquitin-protein ligase, catalyzing polyubiquitination of target proteins 1. The U-box domain enables interaction with ubiquitin-conjugating enzymes (E2s) through a conserved structural motif 2, facilitating substrate ubiquitination and proteasomal degradation. Recent evidence identifies Binding Immunoglobulin Protein (BIP) as a key physiological substrate of UBOX5 3. Clinically, UBOX5 variants show strong association with primary angle-closure glaucoma (PACG), with carriers of rare protein-altering variants demonstrating 2.13-fold increased disease risk 3. Functionally deficient UBOX5 variants are significantly enriched in affected individuals, implicating impaired UBOX5-BIP signaling in glaucoma pathogenesis. Additionally, UBOX5 emerges as a hub gene in atherosclerosis pathogenesis, identified through differential expression analysis in atherosclerotic monocytes 4, suggesting roles in cardiovascular disease. Beyond the protein-coding gene, the antisense lncRNA UBOX5-AS1 demonstrates dysregulation in endometriosis, where ALKBH5-mediated m6A demethylation increases its expression, promoting autophagy, proliferation, and invasion 5. Under hypoxic conditions, HIF-1α signaling upregulates UBOX5-AS1, driving epithelial-mesenchymal transition in endometrial cells 6. These findings position UBOX5 and its regulatory elements as potential therapeutic targets for multiple diseases.