E2F3 activates NF-κB signaling through TRIM26 mediated TAB1 ubiquitination in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with limited therapeutic options. Dysregulated transcriptional networks are key drivers of its aggressive biology. Here, by integrating clinical datasets with mechanistic studies, we performed a family wide systematic analysis of E2F transcription factors and identified E2F3 as a key oncogenic driver with prognostic significance comparable to E2F1. Functional studies showed that E2F3 accelerates PDAC proliferation and xenograft growth. Mechanistically, E2F3 transcriptionally activates the E3 ligase TRIM26, which binds TAB1, promotes K11-linked polyubiquitination, and facilitates TAB1-TAK1 complex formation to engage canonical NF-κB signaling. The SPRY and RING domains of TRIM26 mediate TAB1 interaction and ubiquitination, respectively. TRIM26 depletion attenuated E2F3 induced NF-κB activation and tumor growth, whereas its restoration rescued these effects. Clinically, E2F3, TRIM26, and phosphorylated p65 levels were positively correlated in PDAC tissues, and therapeutic delivery of siTRIM26 recapitulated NF-κB inhibition. These findings uncover an unrecognized E2F3-TRIM26-TAB1/TAK1-NF-κB signaling axis that links cell cycle regulation with inflammatory activation in PDAC and nominate TRIM26 as a druggable vulnerability to therapeutically decouple this oncogenic crosstalk.