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In this study, PTBP3 is found to be significantly overexpressed in peritoneal metastatic tissues of gastric cancer compared to primary tumor tissues, and higher PTBP3 expression correlates with poorer prognosis. Using gastric cancer cells and patient\u2010derived organoids (PDO), the role of PTBP3 in promoting tumor invasion and proliferation is investigated. Mechanistically, through full\u2010length transcriptome sequencing, PTBP3 mediates exon 4 skipping in its target gene COX11, leading to shorter transcripts that impair COX11 protein function, reducing mitochondrial copper content and enabling tumor cells to evade cuproptosis. Antisense oligonucleotide (ASO) drugs targeting the short COX11 transcripts effectively degrade mRNA, disrupting copper homeostasis. In PDO\u2010based xenograft models, exogenous copper ionophores combined with ASO drugs induce excessive copper accumulation in mitochondria, triggering proteotoxic stress and cuproptosis. Overall, PTBP3\u2010mediated exon 4 skipping in COX11 pre\u2010mRNA is critical for tumor cell survival and progression in GCPM, offering potential therapeutic strategies targeting copper metabolism.<\/jats:p>","DOI":"10.1002\/advs.202415983","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T05:41:15Z","timestamp":1745473275000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeting PTBP3\u2010Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8433-1074","authenticated-orcid":false,"given":"Yajing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of General Surgery The First Affiliated Hospital of Soochow University 899 Pinghai Road Suzhou Jiangsu Province 215031 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