Abstract
Background: Gastric cancer (GC), a prevalent and life-threatening malignancy, poses significant challenges in diagnosis and prognosis due to its complex molecular pathogenesis. Identifying novel biomarkers and therapeutic targets is crucial for advancing treatment strategies and improving patient outcomes. This study investigates the role of synaptotagmin-4 (SYT4), recently identified as an oncogene, in GC development. Methods: We integrated proteomic and clinical analyses to evaluate SYT4 expression levels and their correlations with clinical features. Bioinformatic and clinicopathological assessments further validated SYT4's clinical relevance. Through comprehensive in vitro and in vivo experiments-including immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), GST pull-down assays, and TOP/FOP luciferase reporter assays-we delineated SYT4's biological functions and interaction mechanisms. Additionally, we investigated the therapeutic potential of borussertib, a specific SYT4 inhibitor, in suppressing GC tumorigenicity. Results: SYT4 expression was significantly upregulated in GC tissues and strongly correlated with poor prognosis. Functionally, SYT4 drove cell proliferation, promoted cell cycle progression, and suppressed apoptosis in both cellular and animal models. Mechanistic investigations revealed that SYT4 directly interacts with PSMC6 via its C2B domain (amino acids 288-423), and stabilizes PSMC6 protein, thereby activating the Wnt/β-catenin signaling pathway. Notably, borussertib, a targeted SYT4 inhibitor, markedly suppressed SYT4 activity, leading to attenuated GC progression. Conclusion: Our findings demonstrate that SYT4 is a critical driver of GC progression via activation of the Wnt/β-catenin pathway. Moreover, we uncovered a novel mechanism by which borussertib selectively inhibits SYT4's oncogenic activity, providing compelling evidence for its therapeutic potential in gastric cancer treatment.