FBXL8 Stabilizes IκBα and Negatively Regulated NF-κB Activation to Suppress Pancreatic Cancer Progression

The dysregulation of ubiquitin-proteasome system (UPS) causes various diseases including cancer. The NF-κB signaling pathway, a critical regulator of inflammation and cell survival, is constitutively activated in pancreatic cancer (PC), but the role of UPS in its regulation is incompletely elucidated. Here, we found that E3 ubiquitin ligase FBXL8 is downregulated in PC tissues, and associated with poor patient prognosis. Functional experiments show that FBXL8 suppresses PC cells proliferation, migration, and invasion both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, FBXL8 binds to dephosphorylated IκBα (S32/S36) and mediates K63-linked polyubiquitination at the K38 site of IκBα, thereby stabilizing IκBα and inhibiting NF-κB p65 nuclear translocation. Meanwhile, p65 upregulates the transcription factor YY1, which transcriptionally represses FBXL8 expression, thereby forming a FBXL8-NF-κB feedforward regulatory loop. In conclusion, this study reveals that FBXL8 suppresses PC progression by stabilizing IκBα through non-degradative ubiquitination, and its downregulation via the NF-κB-YY1 axis promotes oncogenic progression. The FBXL8-IκBα-NF-κB pathway represents a promising novel therapeutic target for PC.