POM121 (POM121 transmembrane nucleoporin) is an essential transmembrane component of the nuclear pore complex (NPC) that regulates nucleocytoplasmic transport of proteins and RNA. As a structural constituent of the NPC, POM121 facilitates the nuclear import of key transcription factors including E2F1, MYC, c-MYC, AR, and PPARγ through importin-dependent mechanisms 12. The protein's repeat-containing domain anchors NPC components to the pore membrane, with both pore-integrated and soluble (sPOM121) nucleoplasmic forms contributing to cellular function 3. In cancer biology, POM121 has emerged as a critical regulator of tumor progression across multiple malignancies. POM121 overexpression is associated with poor prognosis in colorectal cancer, prostate cancer, non-small cell lung cancer, and neuroendocrine carcinomas 2145. POM121 promotes oncogenic transcription factor nuclear accumulation and activity, including MYC-mediated PD-L1 induction, β-catenin-driven progression, and supports immune evasion mechanisms 43. The protein is stabilized by UCHL1 deubiquitination and can be transcriptionally activated by histone H3K18 lactylation 54. In neurodegenerative diseases, POM121 dysfunction contributes to pathogenesis. Poly-PR toxicity in C9orf72-ALS reduces POM121 expression, impairing nuclear envelope integrity and ATF3 transcription factor localization; the Sigma-1R/POM121/ATF3 axis represents a neuroprotective pathway 6. Conversely, ESCRT-III pathway overactivation in sporadic ALS promotes POM121 reduction and contributes to NPC injury and TDP-43 dysfunction 7. Stress granule assembly disrupts nucleocytoplasmic transport machinery in ALS/FTD 8.