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This study investigated the anti-cancer activities of 30 monomers extracted from Morus alba L. (mulberry) against gastrointestinal cancers. Toxicological assessments revealed that most of the compounds, particularly immunotoxicity, exhibit some level of toxicity, but it is generally not life-threatening under normal conditions. Among these components, Sanggenol L, Sanggenon C, Kuwanon H, 3\u2032-Geranyl-3-prenyl-5,7,2\u2032,4\u2032-tetrahydroxyflavone, Morusinol, Mulberrin, Moracin P, Kuwanon E, and Kuwanon A demonstrate significant anti-cancer properties against various gastrointestinal cancers, including colon, pancreatic, and gastric cancers. The anti-cancer mechanism of these chemical components was explored in gastric cancer cells, revealing that they inhibit cell cycle and DNA replication-related gene expression, leading to the effective suppression of tumor cell growth. Additionally, they induced unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, potentially resulting in DNA damage, autophagy, and cell death. Moracin P, an active monomer characterized as a 2-arylbenzofuran, was found to induce ER stress and promote apoptosis in gastric cancer cells, confirming its potential to inhibit tumor cell growth in vitro and in vivo. These findings highlight the therapeutic potential of Morus alba L. monomers in gastrointestinal cancers, especially focusing on Moracin P as a potent inducer of ER stress and apoptosis.<\/jats:p>","DOI":"10.3390\/ijms25020999","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T11:15:01Z","timestamp":1705317301000},"page":"999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Gastrointestinal Cancer Therapeutics via Triggering Unfolded Protein Response and Endoplasmic Reticulum Stress by 2-Arylbenzofuran"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9618-610X","authenticated-orcid":false,"given":"Kui","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7403-8808","authenticated-orcid":false,"given":"Xin","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Institute of Sericulture and Systems Biology, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhimanyu","family":"Thakur","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0717-2054","authenticated-orcid":false,"given":"Vikramsingh","family":"Gujar","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Okhlahoma State University Center for Health Sciences, Tulsa, OK 74107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1178-1570","authenticated-orcid":false,"given":"Hongjuan","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J. 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