Nuclear KRT19 links the NF-κB-FSCN1 signaling to gastric cancer metastasis.

Tumor metastasis is the leading cause of cancer-related mortality, yet the contribution of keratins to this process remains incompletely understood. Here, integrated single-cell and bulk transcriptomic analyses identify keratin 19 (KRT19) within a migration-activated epithelial program as a gene of potential functional relevance. Clinical datasets and tissue microarrays show that KRT19 expression is markedly elevated in gastric cancer and is strongly associated with aggressive pathological features. Functional assays demonstrate that KRT19 depletion impairs cellular migration, invasion, and three-dimensional spheroid infiltration, while while intrasplenic injection of KRT19-silenced cells into male BALB/c nude mice significantly reduces hepatic metastatic colonization, as monitored by serial bioluminescent imaging. Mechanistically, nuclear KRT19 interacts with hnRNPU to facilitate β-TrCP-mediated ubiquitination and degradation of IκBα, thereby sustaining NF-κB activity. Activated NF-κB directly engages the FSCN1 promoter and enhances its transcription, and FSCN1 restoration partially rescues the migratory and metastatic deficits caused by KRT19 knockdown. Together, these findings define a signaling cascade in which an intermediate filament rewires transcriptional programs to control cytoskeletal remodeling and motility, providing mechanistic insight into gastric cancer dissemination and highlighting epithelial structural proteins as underappreciated drivers of metastasis.