A novel ZNF263-SMOX-ROS-TRIB3 signaling axis drives Wnt/β-catenin activation and metastatic progression in colorectal cancer

Spermine oxidase (SMOX), a key enzyme in polyamine catabolism, has been increasingly linked to tumor progression. However, its regulatory network and biological significance in colorectal Cancer (CRC), particularly in metastasis, remain largely undefined. Integrated transcriptomic analyses of CRC peritoneal metastasis samples, GEO datasets, and TCGA cohorts were performed to determine SMOX expression and prognostic value. Functional assays in vitro and xenograft/peritoneal metastasis models in vivo were used to assess the impact of SMOX knockdown or overexpression. Mechanistic studies included pathway enrichment, Western blotting, Co-IP, and ChIP-qPCR. SMOX was consistently upregulated in CRC tissues and cell lines, and high SMOX expression correlated with advanced stage, lymphatic metastasis, and unfavorable prognosis. Functionally, SMOX depletion markedly suppressed CRC cell proliferation, colony formation, migration, and invasion, and impaired tumor growth and peritoneal dissemination in vivo; SMOX overexpression exerted opposite protumorigenic effects. Mechanistically, SMOX elevated intracellular ROS levels, leading to transcriptional upregulation of the pseudokinase TRIB3. TRIB3 interacted with and suppressed GSK-3β activity, consequently stabilizing β-catenin and activating the Wnt/β-catenin pathway. Moreover, we identified ZNF263 as a previously unrecognized transcriptional activator of SMOX; ZNF263 directly bound to the SMOX promoter and drove its overexpression in CRC. Together, these findings delineate a novel "ZNF263-SMOX-ROS-TRIB3-GSK-3β-β-catenin" axis. Our study reveals SMOX as a critical driver of CRC progression and metastasis through ROS-mediated TRIB3 induction and subsequent Wnt/β-catenin activation, under the upstream regulation of ZNF263. This signaling axis provides new mechanistic insights and highlights SMOX/TRIB3 as promising therapeutic targets in CRC.