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However, whether FLLL32 regulates ferroptosis in colorectal cancer (CRC) and the underlying mechanism remain unclear. Here, using a patient-derived CRC organoid screening platform, we identified FLLL32 as a potent anti-CRC compound. FLLL32 suppressed CRC organoid growth, inhibited CRC cell proliferation and migration in vitro, and inhibited xenograft tumor growth in vivo. In parallel, FLLL32 induced ferroptosis-associated iron accumulation, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial morphological and functional abnormalities. The ferroptosis inhibitor Ferrostatin-1 markedly restored FLLL32-impaired cell viability and reduced ROS, whereas the apoptosis inhibitor Z-VAD-FMK showed weaker protection. These findings suggest that ferroptosis is a major contributor to FLLL32-induced cell death, although apoptotic features are also present. Mechanistically, FLLL32 interacted with STAT3, and Glu638 and Met726 contributed to the FLLL32-STAT3 interaction. FLLL32 also suppressed STAT3 Tyr705 phosphorylation and nuclear signaling, thereby disrupting pSTAT3-mediated transcriptional regulation of glutathione peroxidase 4 (GPX4) and solute carrier family 40 member 1 (SLC40A1), weakening lipid peroxide detoxification and cellular iron efflux, promoting intracellular iron accumulation, and enhancing ferroptosis in CRC cells. These findings define a STAT3-GPX4\/SLC40A1-dependent mechanism underlying the anti-CRC activity of FLLL32 and support further investigation of STAT3-associated ferroptosis regulation as a potential therapeutic vulnerability in CRC.<\/jats:p>","DOI":"10.1186\/s43556-026-00575-5","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:25:39Z","timestamp":1792466739000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Curcumin analogue FLLL32 induces ferroptosis by targeting the STAT3-GPX4\/SLC40A1 axis in colorectal cancer"],"prefix":"10.1186","volume":"7","author":[{"given":"Tong","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqiu","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuye","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaguang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"issue":"3","key":"575_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2022","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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Sci China Life Sci. 2023;66(3):545\u201362. https:\/\/doi.org\/10.1007\/s11427-022-2167-3.","journal-title":"Sci China Life Sci"}],"container-title":["Molecular Biomedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-026-00575-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s43556-026-00575-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-026-00575-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:02:14Z","timestamp":1792526534000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s43556-026-00575-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,20]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["575"],"URL":"https:\/\/doi.org\/10.1186\/s43556-026-00575-5","relation":{},"ISSN":["2662-8651"],"issn-type":[{"value":"2662-8651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,20]]},"assertion":[{"value":"14 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 August 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All experiments involving human specimens were conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of West China Hospital, Sichuan University (Chengdu, China; IRB number: 2023\u20131501). Written informed consent was obtained from all participants. All animal procedures were approved by the Institutional Animal Care and Use Committee of West China Hospital, Sichuan University (approval number: 20250611005).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflict of interest.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"217"}}