The TUBA1B–G3BP2 Axis Sustains p65 Transcriptional Activity to Promote Hepatocellular Carcinoma Progression

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, yet mechanisms sustaining malignant progression remain incompletely defined. Integrative analyses across multiple HCC cohorts identified TUBA1B as one of the most consistently upregulated tubulin isotypes whose high expression associates with poor prognosis and metastasis. In hydrodynamic tail-vein injection (HTVi) models, co-expression of Tuba1b with myr-AKT enhanced liver tumor growth, supporting a tumor-promoting role for Tuba1b in vivo. TUBA1B knockdown suppressed HCC cell proliferation, migration, and invasion in vitro and reduced tumor growth and metastasis in orthotopic models. HTVi-mediated delivery of sgTuba1b suppressed hepatocarcinogenesis in NRasV12/myr-AKT- and MYC/sg-p53 HCC models and prolonged survival in the former, whereas sgTuba1b delivery to normal livers caused no detectable histological abnormalities. Mechanistically, TUBA1B bound and stabilized G3BP2 by restraining TRIM25-dependent K48-linked ubiquitination, thereby promoting G3BP2-IκBα association and sustaining basal NF-κB/p65 transcriptional activity; enforced G3BP2 expression rescued the proliferative and metastatic defects caused by TUBA1B loss. Clinically, combined upregulation of TUBA1B and G3BP2 with elevated p65 activity delineated a high-risk HCC subgroup with the poorest outcomes. Collectively, these findings define a TUBA1B-G3BP2 stability axis that supports malignant phenotypes and highlight a potential therapeutic vulnerability in HCC.