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In this study, a radioresistant (RR) cell line is established to explore the transcriptomic signatures of radioresistance in colorectal cancer (CRC). KEGG enriched pathway analysis demonstrated that ferroptosis is inactivated in RR cells. Further detection confirmed that radiotherapy can promote ferroptosis, and ferroptosis inactivation is one of the hallmarks of radioresistance in CRC. What's more, induction of ferroptosis can restore the radiosensitivity of CRC cells. Then, we performed RNA sequencing to compare gene expression between parental and RR cells, and cells pretreated with or without RSL3. Via high\u2010throughput screening, NUPR1 was identified as a potential candidate for ferroptosis\u2010mediated radioresistance in CRC. CRC cells can acquire radiation resistance by NUPR1\u2010mediated ferroptosis suppression in the NUPR1\u2010overexpressing cell line. More importantly, ZZW\u2010115, an NUPR1 inhibitor, can sensitise RR cells to radiotherapy. Overall, our findings identify ferroptosis inactivation linked with resistance to radiotherapy. Besides, NUPR1 can promote radiation resistance by inhibiting ferroptosis, and targeting NUPR1 may be a potential strategy to relieve radioresistance associated with ferroptosis in CRC.<\/jats:p>","DOI":"10.1111\/jcmm.70519","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T15:56:29Z","timestamp":1743782189000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>NUPR1<\/scp>\n                    Promotes Radioresistance in Colorectal Cancer Cells by Inhibiting Ferroptosis"],"prefix":"10.1111","volume":"29","author":[{"given":"Yimin","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), the Second Affiliated Hospital, Zhejiang University School of Medicine 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