Targeting FAM134B-DDX3X axis inhibiting AKT signaling in hepatocellular carcinoma.

Family with sequence similarity 134, member B (FAM134B), known for its role as an ER-phagy receptor, has been implicated in the promotion of hepatocellular carcinoma (HCC) progression through the activation of the AKT signaling pathway. However, the precise mechanism underlying FAM134B's activation of AKT signaling remains to be elucidated. This study aimed to investigate the interaction between FAM134B and DEAD-box helicase 3 X-linked (DDX3X) and its implications for HCC. We found that FAM134B interacts with DDX3X, preventing its proteasomal degradation by reducing K48-linked polyubiquitination and enhancing K63-linked polyubiquitination. This stabilization of DDX3X is crucial for AKT signaling activation, as DDX3X is known to promote the transcription of Rac Family Small GTPase 1 (Rac1), a key activator of the AKT pathway. Our results confirmed that FAM134B activates AKT signaling through the DDX3X-Rac1-AKT axis in HCC. Furthermore, we observed that DDX3X is upregulated in HCC and contributes to tumor progression. Interestingly, DDX3X not only activates AKT signaling but also increases FAM134B expression by enhancing its transcriptional activity, suggesting a positive feedback loop between these two proteins in HCC. Lastly, we explored the therapeutic potential of combining the DDX3X inhibitor RK-33 with FAM134B knockdown in HCC treatment. Our findings indicate that this synergistic approach may offer a promising strategy for HCC therapy.