NUP54 is a central channel nucleoporin that serves as a structural component of the nuclear pore complex (NPC), facilitating nucleocytoplasmic transport and protein import into the nucleus 1. Beyond its canonical transport role, NUP54 has emerged as a multifunctional protein with roles in genome maintenance and gene regulation. Mechanistically, NUP54 contributes to homologous recombination (HR) repair of DNA double-strand breaks, with depletion increasing radiosensitivity and chromosome 4 1. NUP54 also functions in tissue-specific transposon silencing through the piRNA pathway in Drosophila ovaries 2. In cancer contexts, NUP54 mediates nuclear import of CARM1, which activates Notch2 signaling to promote gastric cancer proliferation 3, while the circular RNA circNUP54 facilitates hepatocellular carcinoma progression via HuR-dependent mRNA stabilization 4. Clinically, biallelic NUP54 variants cause early-onset dystonia with striatal lesions and neurodegeneration, phenotypically similar to NUP62-related disease 5. The pathogenic variants cluster in the C-terminal region that interacts with NUP62, suggesting impaired NPC function underlies neurological disease. These findings establish NUP54 as critical for both nuclear transport and multiple specialized cellular functions, with disease relevance spanning neurodegeneration and cancer progression.