UBXN8 (UBX domain protein 8) is a transmembrane endoplasmic reticulum (ER) protein that functions as a critical cofactor in ER-associated degradation (ERAD). The protein tethers VCP/p97 to the ER membrane via its UBX domain to facilitate efficient degradation of misfolded lumenal proteins 1. UBXN8 contains leucine zipper-like motifs and localizes to the ER membrane with its UBX domain oriented toward the cytoplasm 2. Knockdown of UBXN8 impairs p97 association with the ER membrane and retards degradation of misfolded proteasome substrates 1. Clinically, UBXN8 acts as a tumor suppressor. In hepatocellular carcinoma, aberrant UBXN8 expression following HBV integration functions in a TP53-dependent manner to suppress oncogenic transformation 3. In t(8;21) acute myeloid leukemia, the RUNX1-RUNX1T1 fusion protein epigenetically silences UBXN8 through DNA methylation-mediated heterochromatic silencing; restoring UBXN8 expression inhibits proliferation and promotes cell cycle arrest and differentiation 4. Additionally, UBXN8 shows tissue-specific expression enriched in reproductive tissues, suggesting a reproductive function 5. Population-specific genetic variation in UBXN8 has been identified, with potential implications for ancestry-informative screening 6.