IKBKE-YAP axis-mediated reciprocal inhibition between Hippo and NF-κB pathways complementarily drives liver tumorigenesis

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Abstract Inactivation of the Hippo signaling pathway critically contributes to hepatocellular carcinoma (HCC) tumorigenesis. However, directly targeting YAP, the key downstream effector of this pathway, has yielded limited clinical benefit in HCC. Here, we report that, in response to inflammatory stimuli, besides promoting inflammation, IKBKE inactivates YAP in liver cancer cells through direct interaction. Consequently, inhibition of IKBKE leads to elevated YAP transcriptional activity, which in turn confers resistance to IKBKE blockade. Mechanistically, IKBKE directly phosphorylates YAP, thereby blocking its nuclear translocation and promoting its degradation. As a result, IKBKE depletion sensitizes HCC cells to YAP inhibitors. Conversely, YAP blockade elevates NF-κB signaling via transcriptional induction of IKBKE , contributing to chemoresistance. Notably, combined inhibition of YAP and IKBKE synergistically suppresses tumor growth in both xenograft and C-Myc -driven HCC mouse models. Collectively, we report a bidirectional negative feedback loop between the Hippo and NF-κB pathways in liver cancer, orchestrated by the reciprocal interplay between YAP and IKBKE. This regulatory circuit supports a rational dual-drug strategy combining IKBKE inhibitors with YAP blockade for effective HCC interventions.