{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:28:38Z","timestamp":1785421718426,"version":"3.56.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Wuxi City Social Development Science and Technology Demonstration Project","award":["N20201005"],"award-info":[{"award-number":["N20201005"]}]},{"name":"Tianjin Medical University Cancer Institute and Hospital","award":["TJYXZDXK-009A"],"award-info":[{"award-number":["TJYXZDXK-009A"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSystems"],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Colorectal cancer (CRC) is a common malignant tumor of the digestive system, and chemotherapy resistance often leads to poor patient prognosis. Harmane, a natural indole alkaloid, is found in Leguminosae plants (particularly those of the Crotalaria genus), as well as in mammalian tissues and certain food products. It exhibits potential anticancer activities through multiple mechanisms in various cancers, including liver, breast, and thyroid cancers. However, the role of harmane in the treatment of CRC remains unclear. In this study, we demonstrate that harmane induces cell cycle arrest and apoptosis in CRC cells via the p53\u2013RRM2B axis. Furthermore, at the level of the gut microbiota, harmane reshapes microbial composition, thereby contributing to its anti-tumor effects.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        This study is the first to demonstrate a progressive decline of harmane levels in the gut from healthy individuals to advanced adenoma and CRC patients, suggesting its potential protective role in CRC development. We further found that harmane promotes CRC cell apoptosis via RRM2B-mediated regulation, revealing the underlying molecular mechanism. Moreover,\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        experiments showed that harmane can modulate gut microbial composition and its derived metabolites, and fecal microbiota transplantation experiments indicated that harmane exerts anticancer effects by regulating both the gut microbiota and microbial metabolites. This study proposes a novel therapeutic strategy for CRC, highlighting the importance of incorporating gut microbiota modulation into cancer treatment.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.01704-25","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:01:58Z","timestamp":1781010118000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Harmane induces apoptosis through RRM2B and suppresses colorectal cancer progression"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2620-076X","authenticated-orcid":true,"given":"Guifang","family":"Li","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wuxi Eighth People\u2019s Hospital","place":["Wuxi, China"]},{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuxi Medical College of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Shen","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jifan","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Feng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]},{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuxi Medical College of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangmeng","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]},{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuxi Medical College of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hejia","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]},{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuxi Medical College of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunan","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]},{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuxi Medical College of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiaXuan","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]},{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuxi Medical College of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiangQian","family":"Zheng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0152hn881","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Thyroid and Neck Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Mao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ar02c28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Affiliated Hospital of Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-22-0385"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.64077"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05671-0"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.07.047"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotobiol.2005.02.004"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(91)90305-o"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2022.113376"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2013.12.038"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2020.105353"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-021-06721-2"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/287345"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae811"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng2040"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2503531122"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.649640"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.03.005"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v28.i30.4053"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-00910-9"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008881"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euaf018"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2024.2333790"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03186-19"},{"key":"e_1_3_5_25_2","first-page":"980","article-title":"Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits","volume":"63","author":"Xue L","year":"2003","unstructured":"Xue L, Zhou B, Liu X, Qiu W, Jin Z, Yen Y. 2003. Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res 63:980\u2013986.","journal-title":"Cancer Res"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2656"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05786-4"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.2174\/0115748928357067250512112852"},{"key":"e_1_3_5_29_2","first-page":"19","article-title":"An in vitro evaluation of human DNA topoisomerase I inhibition by Peganum harmala L. seeds extract and its beta-carboline alkaloids","volume":"5","author":"Sobhani AM","year":"2002","unstructured":"Sobhani AM, Ebrahimi SA, Mahmoudian M. 2002. An in vitro evaluation of human DNA topoisomerase I inhibition by Peganum harmala L. seeds extract and its beta-carboline alkaloids. J Pharm Pharm Sci 5:19\u201323.","journal-title":"J Pharm Pharm Sci"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2017.02.008"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.5497"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2025.108557"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202205563"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2023.2236364"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00766-x"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.09.021"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104670"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02569-3"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-024-01890-6"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-020-00596-9"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2022.02.004"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.216039"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.70021"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.116061"}],"container-title":["mSystems"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msystems.01704-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msystems.01704-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T13:03:36Z","timestamp":1784639016000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/msystems.01704-25"}},"subtitle":[],"editor":[{"given":"Sarah L.","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":43,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,21]]}},"alternative-id":["10.1128\/msystems.01704-25"],"URL":"https:\/\/doi.org\/10.1128\/msystems.01704-25","relation":{},"ISSN":["2379-5077"],"issn-type":[{"value":"2379-5077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"2025-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01704-25"}}