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The xenograft tumor model was established, and the inhibition effect of GNA were evaluated by observing the tumor growth. The endoplasmic reticulum (ER) of HCT116 was observed by using the ER tracker. The TargrtScan database was used to predict the miRNA binding sites. The level of miRNA with GNA treatment was explored by real\u2010time quantitative PCR. The effect of ferroptosis were evaluated by detect the expression of reactive oxygen species (ROS), intracellular ferrous iron (Fe<jats:sup>2+<\/jats:sup>), malondialdehyde (MDA), glutathione (GSH), subunit solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase (GPX)4, transferrin, and ferritin by Western blot.\u00a0GNA isolated from gamboge can inhibit the growth and proliferation of CRC cell lines in a concentration\u2010dependent manner. GNA activated ER stress by upregulating miR\u20101291, and miR\u20101291 targeted the forkhead box protein A2 (FOXA2). GNA also induced ROS production and mediated the Fenton reaction by activating transferrin to increase Fe<jats:sup>2+<\/jats:sup>, thus inducing ferroptosis. In addition, GNA could induce ferroptosis through the depletion of GSH and GPX4. Furthermore, GNA treatment regulated iron metabolism by activating AMPK\u03b1\/SLC7A11\/GPX4 signaling. In conclusion, GNA activated ER stress via miR\u20101291 and induced ferroptosis in CRC cells and might be a new inducer of ferroptosis, which can expand the efficacy of chemotherapy drugs.<\/jats:p>","DOI":"10.1002\/cbin.12072","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T20:50:28Z","timestamp":1689886228000},"page":"1813-1824","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR\u20101291\/FOXA2 and AMPK\u03b1\/SLC7A11\/GPX4 axis in colorectal cancer"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7290-8305","authenticated-orcid":false,"given":"Xiaoqi","family":"Ma","sequence":"first","affiliation":[{"name":"Experiment Center for Science and Technology Shanghai University of Traditional Chinese Medicine  Shanghai P.R. 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