{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:32:25Z","timestamp":1789428745263,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2025ZDZX0047"],"award-info":[{"award-number":["2025ZDZX0047"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2025ZDZX0047"],"award-info":[{"award-number":["2025ZDZX0047"]}],"id":[{"id":"https:\/\/ror.org\/04323m874","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tumor microenvironments, particularly hypoxia and inflammation, heavily influence colorectal cancer (CRC) pathogenesis by altering polyamine metabolism. Identifying natural compounds targeting these vulnerabilities remains critical. Integrating untargeted metabolomics, network pharmacology, and a human endogenous metabolite library screen, we identified apigenin (API) as a potent anti-CRC candidate. API significantly inhibited the proliferation, migration, and invasion of RKO and HCT116 cells in vitro and suppressed xenograft tumor growth in vivo. Crucially, high-throughput screening revealed that polyamines rescued CRC cells from API-induced cytotoxicity. Mechanistically, API exerts its effects by dismantling a newly identified HIF-1\u03b1\/SMOX positive feedback loop. In CRC, HIF-1\u03b1 transcriptionally activates spermine oxidase (SMOX), while SMOX-driven polyamine metabolism fuels the TLR4\/MyD88 inflammatory cascade to continuously stabilize HIF-1\u03b1. API acts as a \u201ccircuit breaker\u201d for this axis, significantly reducing the spermidine\/spermine ratio and downregulating inflammatory signaling. Ultimately, API effectively remodels polyamine metabolism and suppresses CRC progression by disrupting the HIF-1\u03b1\/SMOX and TLR4\/MyD88 pathways, offering a novel metabolic mechanism for API in CRC therapy.<\/jats:p>","DOI":"10.3390\/ijms27073261","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T02:06:21Z","timestamp":1775441181000},"page":"3261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1\u03b1\/SMOX Positive Feedback Loop to Suppress Tumor Progression"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7873-7921","authenticated-orcid":false,"given":"Zhengkun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"},{"name":"Chongqing Advanced Pathology Research Institute, Jinfeng Laboratory, Chongqing 401329, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9253-9171","authenticated-orcid":false,"given":"Ruiman","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuxu","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoru","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-3425","authenticated-orcid":false,"given":"Ji","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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