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Upregulation of deoxypyrimidine synthesis is one of the important reasons for pancreatic cancer cells to be resistant to gemcitabine, however, the specific mechanism leading to increased deoxypyrimidine synthesis in pancreatic cancer cells is still unclear. Ribonucleotide reductase M2 subunit (RRM2) is overexpressed through unclear mechanisms in many types of human cancer significantly affects sensitivity to various chemotherapy treatments. Here, we found that high expression of enolase-1 (ENO1) is closely related to gemcitabine resistance in pancreatic cancer patients. Cellular experiments and in vivo experiments confirmed that ENO1 increases the resistance of pancreatic cancer to gemcitabine without relying on its glycolytic enzyme activity. Mechanistically, ENO1 competitively binds to RRM2 with ubiquitin E3 ligase STUB1, thereby weakening the ubiquitination and degradation of RRM2 by STUB1. This ENO1-mediated aggregation of RRM2 protein increases the synthesis of dNTPs in pancreatic cancer cells, enhancing the resistance of pancreatic cancer to gemcitabine. Our study reveals a role of ENO1 in pancreatic cancer via RRM2-STUB1 axis and provides a scientific basis for the development of new therapeutic strategies targeting ENO1.<\/jats:p>","DOI":"10.1038\/s41419-025-08061-6","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T05:53:14Z","timestamp":1766814794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["ENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer"],"prefix":"10.1038","volume":"17","author":[{"given":"Yongning","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyu","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dijie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Futang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4294-4275","authenticated-orcid":false,"given":"Changhao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1434-2170","authenticated-orcid":false,"given":"Zhiwei","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-9416","authenticated-orcid":false,"given":"Chao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,27]]},"reference":[{"key":"8061_CR1","first-page":"17","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A. 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