UBE2J1 is an endoplasmic reticulum-anchored ubiquitin-conjugating enzyme (E2) that regulates protein degradation through polyubiquitination in multiple cellular contexts. As a core component of the HRD1 ERAD complex, UBE2J1 is recruited by the SEL1L-HRD1 interaction to facilitate ER-associated protein degradation 1. UBE2J1 partners with E3 ligases including TRIM25, HRD1, and RNF26 to mediate Lys-48-linked ubiquitination of diverse substrates, and its activity is regulated by MAPK-dependent phosphorylation at serine-184 during ER stress 2. In viral pathogenesis, UBE2J1 promotes Dengue virus replication by negatively regulating interferon-beta signaling through IRF3 ubiquitination and degradation 3. In cancer, UBE2J1 shows context-dependent roles: it functions as a tumor suppressor in colorectal cancer by targeting RPS3 for degradation and inactivating NF-κB signaling 4, while acting as an oncogene in endometrial and high-grade serous ovarian cancers via PI3K/AKT pathway activation 56. Notably, UBE2J1 is essential for androgen receptor degradation in prostate cancer, and its loss (5-15% of cases) confers antiandrogen resistance 7. Additionally, the ER-embedded UBE2J1/RNF26 complex spatiotemporally controls endolysosomal trafficking through p62 ubiquitination 8, highlighting UBE2J1's role in organellar communication and receptor signaling termination.