{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:26:30Z","timestamp":1785795990792,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003621","name":"Ministry of Science and ICT","doi-asserted-by":"publisher","award":["KGM5482221"],"award-info":[{"award-number":["KGM5482221"]}],"id":[{"id":"10.13039\/501100003621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Although the tumor bulk is initially reduced by 5-fluorouracil (5-FU), chemoresistance developed due to prolonged chemotherapy in colorectal cancer (CRC). The enrichment of cancer stem cells (CSCs) and the infiltration of tumor-associated macrophages (TAMs) contribute to chemoresistance and poor outcomes. A docosahexaenoic acid derivative developed by our group, 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), exerts antitumor effects against TAMs infiltration and CSCs enrichment in our previous study. The current study aimed to investigate whether diHEP-DPA was able to overcome chemoresistance to 5-FU in CRCs, together with the potential synergistic mechanisms in a CT26-BALB\/c mouse model. Our results suggested that although 5-FU inhibited tumor growth, 5-FU enriched CSCs via the WNT\/\u03b2-catenin signaling pathway, resulting in chemoresistance in CRCs. However, we revealed that 5-FU promoted the infiltration of TAMs via the NF-kB signaling pathway and improved epithelial\u2013mesenchymal transition (EMT) via the signal transducer and activator of the transcription 3 (STAT3) signaling pathway; these traits were believed to contribute to CSC activation. Furthermore, supplementation with diHEP-DPA could overcome drug resistance by decreasing the CSCs, suppressing the infiltration of TAMs, and inhibiting EMT progression. Additionally, the combinatorial treatment of diHEP-DPA and 5-FU effectively enhanced phagocytosis by blocking the CD47\/signal regulatory protein alpha (SIRP\u03b1) axis. These findings present that diHEP-DPA is a potential therapeutic supplement to improve drug outcomes and suppress chemoresistance associated with the current 5-FU-based therapies for colorectal cancer.<\/jats:p>","DOI":"10.3390\/md21020080","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T04:22:16Z","timestamp":1674620536000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["7S,15R-Dihydroxy-16S,17S-epoxy-docosapentaenoic Acid Overcomes Chemoresistance of 5-Fluorouracil by Suppressing the Infiltration of Tumor-Associated Macrophages and Inhibiting the Activation of Cancer Stem Cells in a Colorectal Cancer Xenograft Model"],"prefix":"10.3390","volume":"21","author":[{"given":"Yan","family":"Su","sequence":"first","affiliation":[{"name":"Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si 56212, Republic of Korea"},{"name":"Department of Bioactive Material Sciences, The Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju-si 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hack Sun","family":"Choi","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju-si 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Hyun","family":"Choi","sequence":"additional","affiliation":[{"name":"Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si 56212, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Sik","family":"Kim","sequence":"additional","affiliation":[{"name":"Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon-si 34141, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-4224","authenticated-orcid":false,"given":"Yong-Suk","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Bioactive Material Sciences, The Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju-si 54896, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Woo","family":"Seo","sequence":"additional","affiliation":[{"name":"Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si 56212, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer Statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. 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