Gemcitabine activates the Hippo signaling pathway and suppresses tumor growth by stabilizing large tumor suppressor kinase 2 through the hypoxia‐inducible factor 1‐alpha/ubiquitin protein ligase E3 component N‐recognin 5 axis

To investigate the molecular mechanism by which gemcitabine (GEM) inhibits ovarian cancer (OC) progression, focusing on the hypoxia‐inducible factor 1‐alpha (HIF1A)/UBR5/LATS2 axis and Hippo pathway. Bioinformatics analysis of gene expression omnibus datasets identified HIF1A‐associated modules. Transcriptional regulation of UBR5 by HIF1A was validated via ChIP‐PCR and dual‐luciferase assays. Anti‐tumor effects of GEM were assessed in OC cell lines and an orthotopic mouse model using functional assays (CCK‐8, transwell), Western blot, Co‐IP, and ubiquitination analysis. HIF1A transcriptionally upregulates UBR5 in OC. GEM downregulated the HIF1A/UBR5 axis, suppressing OC cell proliferation, migration, and invasion. Mechanistically, UBR5 promoted LATS2 ubiquitination and degradation. GEM inhibited this interaction, stabilizing LATS2, activating the Hippo pathway, and suppressing downstream YAP1/FGFR1 signaling. In vivo, GEM inhibited tumor growth and downregulated HIF1A, UBR5, and FGFR1. GEM suppresses OC progression by targeting the HIF1A/UBR5 axis, which subsequently stabilizes LATS2, activates the Hippo pathway, and inhibits YAP1/FGFR1 signaling, revealing a novel therapeutic mechanism.