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In colorectal cancer, conventional fractionation (1.8\u2009~\u20092.0\u00a0Gy daily) is typically used for treatment. Nevertheless, there is a paucity of research investigating the potential implications of radiation therapy-induced alterations in the expression levels of regulatory genes on resistance to chemotherapy agents. Herein, we explored the mechanism by which conventional fractionation drives 5-fluorouracil (5-FU) resistance and metformin (Met) rescued 5-FU resistance in CRC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and materials<\/jats:title>\n                    <jats:p>RNA sequencing, differential genes expression analysis was performed to identify the 5-FU resistance genes after irradiation (according to the convention of cell irradiation, 2\u00a0Gy \u00d7 8 scheme was selected). Drug sensitivity assay, immunofluorescence staining, folate analogs concentration measurement was used to explore the biological function of histocompatibility minor 13 (HM13) and \u03b3-Glutamyl Hydrolase (GGH). Combined chemosensitivity test and xenograft mouse model has been used to gain insights into the underlying clinical value of the combination of 5-FU and Met.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The conventional fractionation scheme (2\u00a0Gy \u00d7 8) induced resistance to 5-FU in the CRC cell line HCT-15, accompanied by an elevated RNA expression level of peptidase HM13. Mechanistically, the increased expression of HM13 caused an abnormal shearing of the N-terminal signal peptide of \u03b3-Glutamyl Hydrolase (GGH), which resulted in decreased intracellular content of 5, 10-methylenetetrahydrofolate (5,10-CH\n                      <jats:sub>2<\/jats:sub>\n                      -THF).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We revealed a new mechanism of 5-FU resistance induced by irradiated with 2\u00a0Gy \u00d7 8 through the HM13-GGH-5,10-CH\n                      <jats:sub>2<\/jats:sub>\n                      -THF axis. The synergistic effect of Met and 5-FU can rescue 5-FU resistance after conventional fractionated irradiation. In summary, this work will help to reveal the mechanisms of IR-induced 5-FU resistance, which is important for finding new therapeutic targets and improving the efficacy of chemotherapy regimens after radiotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01206-5","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T05:02:46Z","timestamp":1747803766000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Metformin reverses 5-FU resistance induced by radiotherapy through mediating folate metabolism in colorectal cancer"],"prefix":"10.1186","volume":"31","author":[{"given":"Shuxuan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanliang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shisuo","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaochong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"issue":"1","key":"1206_CR12","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/s41420-024-02040-0","volume":"11","author":"G Acharya","year":"2024","unstructured":"Acharya G, Mani C, Sah N, et al. 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