GNAZ suppresses lung adenocarcinoma progression through HUWE1-mediated KIF11 ubiquitination and modulates the response to osimertinib

Osimertinib is a standard targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD), yet substantial variation in treatment response remains a clinical problem. Here, we investigated the role of GNAZ, a heterotrimeric G-protein α-subunit that remains poorly characterized in lung cancer. Analyses of TCGA and GEO datasets, together with validation in clinical specimens, showed that GNAZ expression is reduced in LUAD and that higher GNAZ levels are associated with longer overall survival. Functionally, GNAZ overexpression suppressed LUAD cell proliferation, migration, invasion, and xenograft growth, whereas GNAZ depletion produced the opposite effects. Transcriptomic and proteomic analyses identified KIF11 as a functionally relevant downstream effector. Mechanistically, GNAZ associated with KIF11 and facilitated HUWE1-dependent KIF11 ubiquitination and proteasomal degradation, as supported by co-immunoprecipitation, cycloheximide-chase, MG132 rescue, ubiquitination, and HUWE1-depletion experiments. This was accompanied by reduced Wnt/β-catenin signaling and attenuation of mesenchymal features. In both cell-based and in vivo LUAD models, GNAZ also increased the antitumor effect of osimertinib, while KIF11 restoration partially counteracted these effects. Upstream analysis further identified KLF5 as a candidate negative regulator of GNAZ transcription. Together, these findings establish a GNAZ–HUWE1/KIF11 regulatory axis that limits LUAD progression and modulates osimertinib responsiveness, providing a mechanistic basis for further investigation of this pathway in EGFR-targeted therapy. This study identifies GNAZ as a tumor suppressor in lung adenocarcinoma. GNAZ facilitates HUWE1-dependent ubiquitination and proteasomal degradation of KIF11, thereby attenuating Wnt/β-catenin signaling and suppressing mesenchymal features and tumor growth. This axis also influences the antitumor response to osimertinib in our LUAD models. Upstream, KLF5 emerged as a candidate negative regulator of GNAZ transcription, although direct regulation remains to be established. Together, these findings establish a GNAZ–HUWE1/KIF11 axis linking KIF11 stability to Wnt/β-catenin signaling, LUAD progression, and osimertinib responsiveness. Whether this pathway also contributes to acquired osimertinib resistance remains to be determined in clinically relevant resistant models.