{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:12:07Z","timestamp":1790327527626,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81972215"],"award-info":[{"award-number":["81972215"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>As a pivotal metabolic enzyme, cysteine dioxygenase type 1 (CDO1) exerts tumour\u2010suppressive effects across diverse tumour types, and its expression is strongly correlated with clinical prognosis. However, the molecular mechanisms underlying CDO1\u2010mediated tumour suppression in gastric cancer (GC), its relationship with the tumour\u2010associated immune microenvironment, and pharmacological strategies to restore its expression remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CDO1 expression and prognosis were evaluated by multi\u2010omics and tissue microarray analyses. Tumour microenvironment and immune infiltration were analyzed using ESTIMATE and ssGSEA. Downstream pathways and interacting proteins were identified by transcriptomics, co\u2010immunoprecipitation, and GST pull\u2010down. CDO1 function was assessed by proliferation, apoptosis, and migration assays in gain\u2010 and loss\u2010of\u2010function models. In vivo tumorigenesis and CDO1\u2010dependent decitabine efficacy were evaluated by subcutaneous xenografts. Patient\u2010derived organoids were used to assess decitabine sensitivity and 5\u2010FU synergy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with normal controls, CDO1 expression was notably decreased in GC tissues, and its low expression was strongly linked to unfavourable prognosis, supporting its utility as a biomarker for prognosis. Elevated CDO1 levels correlated with an immune\u2010active tumour microenvironment and reduced metastatic signatures. Mechanistically, CDO1 directly bound to PI3K p85\u03b1, disrupting p85\u03b1\u2010p110\u03b1 dimerization, thereby attenuating PI3K\/AKT phosphorylation and downregulating THBS1 expression. CDO1 overexpression led to reduced proliferation, invasiveness, and EMT, accompanied by increased apoptosis. These effects were reversed by PI3K activation or THBS1 co\u2010overexpression. Decitabine was identified as an agent that epigenetically restores CDO1 expression. Critically, CDO1 knockdown significantly attenuated the anti\u2010tumour efficacy of decitabine in vivo, confirming that decitabine acts primarily through CDO1 reactivation. Decitabine synergized with 5\u2010FU in both organoids and xenografts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data identify CDO1 as both a biomarker for prognosis and a tumour suppressor in gastric cancer. They reveal a CDO1\u2013PI3K\/AKT\u2013THBS1 signalling axis and support the epigenetic reactivation of CDO1 by decitabine as a translatable therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>CDO1 is frequently downregulated in gastric cancer and serves as an independent favourable prognostic biomarker.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CDO1 directly binds PI3K p85\u03b1, disrupting p85\u03b1\u2013p110\u03b1 dimerization to suppress the PI3K\/AKT\u2013THBS1 signalling axis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Decitabine epigenetically restores CDO1 expression, and its anti\u2010tumour activity is critically CDO1\u2010dependent in vivo.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Combining decitabine with 5\u2010FU synergistically overcomes gastric cancer growth in patient\u2010derived organoids and subcutaneous xenograft models.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70784","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:41:09Z","timestamp":1788158469000},"source":"Crossref","is-referenced-by-count":0,"title":["CDO1 as a prognostic biomarker and therapeutic target in gastric cancer: Mechanistic insights into the PI3K\/AKT\u2010THBS1 axis and epigenetic reactivation by decitabine"],"prefix":"10.1002","volume":"16","author":[{"given":"Fazhi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5985-047X","authenticated-orcid":false,"given":"Runkai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazhe","family":"Wen","sequence":"additional","affiliation":[{"name":"School of 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