DDX39B (DExD-box helicase 39B) is a DEAD-box RNA helicase with dual roles in RNA metabolism and cancer progression. As a core component of the TREX complex, DDX39B functions in mRNA splicing, export, and nuclear mRNP remodeling 12. The TREX-2 complex contains a conserved trigger loop that facilitates DDX39B release from mRNPs through interactions that split its RecA domains, enabling completion of mRNA export 2. Beyond canonical RNA processing, DDX39B promotes cancer metastasis across multiple tumor types through protein-protein interactions independent of its helicase activity. In colorectal cancer, DDX39B stabilizes PKM2 and recruits importin α5 for its nuclear translocation, activating glycolytic reprogramming 3. In non-small cell lung cancer, TRIM28-mediated K63-linked ubiquitination of DDX39B enhances its stability, promoting E-cadherin degradation and β-catenin signaling 4. DDX39B also regulates circRNA nuclear export through SUMOylation-dependent mechanisms affecting metastasis 5. In pancreatic cancer, DDX39B interacts with RETSAT to resolve R-loops and promote replication fork restart under hypoxic stress 6. Notably, biallelic DDX39B variants cause a novel neurodevelopmental syndrome featuring developmental delay, hypotonia, epilepsy, and microcephaly, with loss-of-function mechanisms demonstrated in model organisms 7. DDX39B represents an emerging therapeutic target for cancer and neurodevelopmental disorders.