Targeting GALNT7 Disrupts the TAZ O-GalNAcylation Feedback Loop to Suppress Gallbladder Cancer Progression

Gallbladder cancer (GBC) is a lethal malignancy with limited therapeutic options and dismal prognosis. Identifying the factors driving GBC progression is crucial for developing potent preventive and therapeutic approaches. Here, using quantitative proteomics, we identify GALNT7 as the most significantly upregulated glycosyltransferase in GBC tissues, associated with adverse clinical outcomes. Mechanistically, GALNT7 physically interacts with TAZ and catalyzes O-GalNAcylation at Ser307, thereby inhibiting K48-linked ubiquitination through the recruitment of the deubiquitinase USP7 and stabilizing the TAZ protein. This post-translational modification promotes TAZ accumulation and subsequent activation of TEAD1-mediated transcription, which in turn upregulates GALNT7 expression, thereby establishing a self-reinforcing oncogenic feedback loop. Disruption of TAZ O-GalNAcylation via the S307A mutation abrogates its oncogenic activity and attenuates GALNT7-driven tumor progression. Importantly, structure-based drug-repurposing screens identified the PARP inhibitor Olaparib as a direct GALNT7 antagonist that effectively inhibits TAZ O-GalNAcylation and demonstrates potent anti-tumor efficacy against GBC both in vitro and in vivo. Collectively, our findings reveal a glycosylation-dependent regulatory axis that drives GBC progression and establish GALNT7-TAZ signaling as a tractable therapeutic target.