UBQLN4 is a proteasomal shuttle factor that regulates protein degradation through its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains. It binds polyubiquitin chains on target proteins and facilitates their delivery to the 26S proteasome, including mislocalized transmembrane proteins and protein aggregates. UBQLN4 also functions as a key regulator of DNA damage response by repressing homologous recombination repair; following ATM phosphorylation, it binds ubiquitinated MRE11 at sites of double-strand breaks, promoting its proteasomal degradation and redirecting repair toward non-homologous end joining. Additionally, UBQLN4 acts as an adapter protein that recruits UBQLN1 to autophagosomes, facilitating autophagosome maturation and clearance of protein aggregates during proteotoxic stress. Clinically, UBQLN4 shows contradictory roles across cancer types. In gastric cancer, UBQLN4 functions as a tumor suppressor through p53-dependent and p53-independent stabilization of p21, inducing cell cycle arrest 1. Conversely, UBQLN4 is amplified and overexpressed in aggressive tumors including liver, breast, ovarian, lung, and esophageal cancers, where high expression predicts poor prognosis in 20 of 32 cancer types and promotes proliferation via the PI3K/AKT pathway 2 3. In non-small cell lung cancer and mesothelioma, UBQLN4 overexpression drives tumorigenesis and resistance to chemotherapy, but sensitizes tumors to poly(ADP-ribose) polymerase inhibitors (PARPi) due to impaired homologous recombination repair 4. A disease-associated variant in UBQLN4 causes autosomal recessive genome instability and impairs motor axon morphogenesis in amyotrophic lateral sclerosis 5. UBQLN4 stabilizes the immune checkpoint protein PD-L1; suppressing UBQLN4 with albendazole promotes PD-L1 degradation and enhances immunotherapy response in melanoma and lung cancer models 6.