POM121 is an essential transmembrane nucleoporin that anchors nuclear pore complex (NPC) components to the pore membrane and regulates nucleocytoplasmic transport of cargo proteins including transcription factors. The gene localizes to the nuclear envelope and its repeat-containing domain facilitates binding and transport of proteins into and out of the nucleus. In cancer, POM121 promotes disease progression through multiple mechanisms. In prostate cancer, POM121 enhances importin-dependent nuclear transport of oncogenic transcription factors E2F1, MYC, and the androgen receptor (AR), driving tumor aggressiveness 1. A soluble nucleoplasmic form of POM121 (sPOM121) reprograms gene expression by interacting with chr7 remodelers, activating β-catenin-driven transcriptional programs and immune evasion in metastatic prostate cancer 2. In non-small cell lung cancer, H3K18 lactylation activates POM121 transcription, which enhances MYC nuclear import and PD-L1 expression to promote immune escape 3. POM121 overexpression is associated with poor outcomes in colorectal cancer and metabolic diseases; silencing POM121 enforces nuclear accumulation of PPARγ, activating tumor-suppressive genes 4. In neuroendocrine carcinomas, UCHL1 stabilizes POM121 to promote progression; the UCHL1 inhibitor LDN-57444 combined with cisplatin reduces tumor growth 5. In neurodegeneration, POM121 dysfunction contributes to disease pathogenesis. Poly-PR toxicity in C9ORF72-linked ALS reduces POM121 expression and compromises nuclear envelope integrity; Sigma-1 receptor stabilizes POM121 to preserve the neuroprotective transcription factor ATF3 6. POM121 reduction directly links NPC injury to TDP-43 nuclear loss, a hallmark of ALS; restoring POM121 in patient-derived neurons corrects TDP-43-associated gene expression changes 7. In sporadic ALS, CHMP2B-dependent overactivation of ESCRT-III surveillance pathways reduces POM121, contributing to NPC damage and TDP-43 mislocalization 8.