JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer

• JOSD1 is upregulated in gastric cancer and correlates with advanced stage and poor prognosis. • JOSD1 functions as a deubiquitinase that stabilizes SULF1 by removing ubiquitin chains. • Stabilized SULF1 directly binds FZD1 to facilitate Wnt7B–FZD1 coupling and activate Wnt/β-catenin signaling. • JOSD1-driven oncogenic effects are strictly dependent on SULF1 stabilization. • Targeting the JOSD1–SULF1–Wnt7B/FZD1 axis represents a potential therapeutic strategy for gastric cancer. Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor–ligand engagement within this pathway remain insufficiently characterized. Comprehensive analyses of GC cohorts and tissue microarrays were performed to evaluate Josephin Domain Containing 1 (JOSD1) expression and its clinical significance. The impact of JOSD1 on cell proliferation, migration, invasion, apoptosis, and epithelial mesenchymal transition (EMT) was examined in vitro employing CCK-8, colony formation, Transwell, flow cytometry, Western blotting, and immunofluorescence assays. Subcutaneous xenograft models were used to assess the effects of JOSD1 on tumor growth in vivo. Mechanistic studies, including co-immunoprecipitation, ubiquitination, and rescue experiments, were employed to elucidate the molecular relationship between JOSD1, Heparan sulfate 6-O-endosulfatase 1 (SULF1), and the Wnt7B/FZD1/β-catenin signaling axis. JOSD1 expression was markedly elevated in GC tissues (log₂ FC > 1, FDR < 0.05) and correlated with advanced stage (P < 0.05) and poor patient prognosis (HR > 1, log-rank P < 0.05). Functionally, JOSD1 promoted GC cell proliferation, invasion, and EMT, while inhibiting apoptosis (P < 0.05). Mechanistically, JOSD1 functioned as a critical deubiquitinase that stabilized SULF1. Stabilized SULF1 directly bound the Wnt co-receptor Frizzled class receptor 1 (FZD1) and facilitated Wnt7B–FZD1 complex formation (P < 0.05), thereby activating canonical Wnt/β-catenin signaling and inducing β-catenin nuclear accumulation (P < 0.05). Ubiquitination and rescue assays confirmed that JOSD1-driven oncogenic effects were strictly dependent on SULF1 stabilization (P < 0.05). In vivo modulation of the JOSD1–SULF1 axis significantly altered tumor growth, apoptotic activity, EMT marker expression, and Wnt pathway activation (P < 0.05). JOSD1 functions as a critical deubiquitinase that stabilizes SULF1 to activate Wnt/β-catenin signaling, thereby driving GC progression. Targeting the JOSD1-SULF1-Wnt7B/FZD1/β-catenin axis may provide a promising therapeutic strategy for patients with GC. The graphical abstract was prepared using Figdraw ( www.figdraw.com ) under an official academic license.