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Functional analyses revealed that DPP7 promotes CRC cell proliferation and inhibits apoptosis, while its depletion enhances natural killer (NK) cell\u2010mediated cytotoxicity against tumour cells. Mechanistically, we identified a previously unknown role of DPP7 in suppressing disulfidptosis, a novel form of regulated cell death characterised by excessive formation of intracellular disulfide bonds. DPP7 overexpression protected CRC cells from glucose deprivation\u2010induced disulfidptosis, as evidenced by reduced disulfide bond formation in cytoskeletal proteins including drebrin, FLNA and FLNB. Furthermore, we discovered that DPP7 physically interacts with glutathione peroxidase 4 (GPX4), a key regulator of cellular redox homeostasis, and stabilises GPX4 protein without affecting its mRNA expression. GPX4 restoration in DPP7\u2010depletion cells reversed the enhanced sensitivity to both disulfidptosis and NK cell\u2010mediated killing, while GPX4 depletion abolished the protective effect of DPP7 overexpression. Our findings unveil a novel DPP7\u2010GPX4 axis in regulating disulfidptosis and immune evasion in colorectal cancer, providing potential therapeutic targets for CRC treatment. Targeting this pathway may simultaneously inhibit tumour cell survival mechanisms and enhance immune\u2010mediated tumour elimination.<\/jats:p>","DOI":"10.1111\/jcmm.70660","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T11:16:02Z","timestamp":1751022962000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["<scp>DPP7<\/scp> Promotes Colorectal Cancer Progression Through <scp>GPX4<\/scp>\u2010Dependent Suppression of Disulfidptosis and Immune Evasion"],"prefix":"10.1111","volume":"29","author":[{"given":"Ruibing","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes The Fifth Affiliated Hospital, Guangzhou Medical University  Guangzhou Guangdong People's Republic of China"},{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital, Sun Yat\u2010Sen University  People's Republic of China"},{"name":"Biomedical Innovation Center The Sixth Affiliated Hospital, Sun Yat\u2010Sen University  People's Republic of China"},{"name":"Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital Sun Yat\u2010Sen University  People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyou","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital, Sun Yat\u2010Sen University  People's Republic of China"},{"name":"Biomedical Innovation Center The Sixth Affiliated Hospital, Sun Yat\u2010Sen University  People's Republic of China"},{"name":"Department of General Surgery (Stomach Surgery), The Sixth Affiliated Hospital Sun Yat\u2010Sen University  People's Republic of 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