Targeting Exportin-1 in Cancer: From Nuclear Export to Oncogenic Transcriptional Hubs.

Maintaining cellular homeostasis requires precise coordination of molecular trafficking between the nucleus and the cytoplasm. Central to this process is the nucleocytoplasmic transport system, which governs the spatial distribution of proteins and RNA. Exportin-1 (XPO1), also known as chromosome region maintenance 1 (CRM1), is the principal nuclear export receptor responsible for the transport of hundreds of cargo proteins bearing leucine-rich nuclear export signals. In a wide range of malignancies, XPO1 is frequently dysregulated through overexpression or recurrent somatic mutations. This dysregulation results in inappropriate cytoplasmic sequestration of tumor suppressor proteins and other regulatory factors, thereby facilitating oncogenic signaling and malignant transformation. Cancer cells consequently become highly dependent on XPO1-mediated nuclear export, positioning XPO1 as a rational therapeutic target. Consistent with this concept, selective inhibitors of nuclear export, such as selinexor, have demonstrated clinical efficacy, received regulatory approval for the treatment of multiple myeloma and diffuse large B-cell lymphoma, and are currently being evaluated in clinical trials for solid tumors. Beyond the canonical transport function, accumulating evidence indicates that XPO1 performs noncanonical roles as a chromatin-associated scaffold that supports the assembly of oncogenic transcriptional hubs and phase-separated biomolecular condensates. These structures integrate nuclear transport machinery with transcriptional regulatory complexes to drive aberrant gene expression programs, particularly in leukemias harboring NPM1 mutations, NUP98 fusions, or UBTF tandem duplications. Disruption of these hubs through XPO1 inhibition represents a therapeutic strategy that extends beyond simple nuclear retention of tumor suppressors, potentially reprogramming malignant transcriptional states. This review outlines the physiological roles of XPO1 as a nuclear exporter and chromatin regulator, examines the pathological consequences of its dysregulation in cancer, summarizes current therapeutic strategies and their clinical outcomes, and discusses emerging evidence for noncanonical functions of XPO1 in nuclear organization and transcriptional regulation.