{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:00:41Z","timestamp":1785128441133,"version":"3.55.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>While the involvement of ferroptosis in the pathological progression of chronic inflammatory bowel disease (IBD) is recognized, the specific regulatory capacity of the natural derivative Atractylenolide I (ATT-I) within this metabolic framework is not yet fully elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate how ATT-I alleviates IBD by modulating ferroptosis via targeting carbonic anhydrase IX (CA9).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To determine the therapeutic potential of ATT-I, a murine model of colitis was established via dextran sulfate sodium (DSS) administration. Mice were treated with different doses of ATT-I. At the end of the experiment, colon tissues and serum were collected for histological analysis, inflammatory cytokine measurement, and ferroptosis marker evaluation. Erastin (ferroptosis inducer) and adenovirus associated virus 9 (AAV9)-mediated CA9 silencing was applied to assess its role in ATT-I efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Medium and high doses of ATT-I significantly alleviated DSS-induced colitis symptoms by reducing histological damage, preventing colon shortening, decreasing spleen index and cytokine levels, and improving epithelial integrity. ATT-I inhibited ferroptosis by upregulating GPX4 and SLC7A11 and downregulating COX-2 and ACSL4. Notably, co-administration of Erastin reversed the protective effects of ATT-I. Network pharmacology and molecular docking suggested CA9 as a putative binding target of ATT-I which was confirmed by CETSA demonstrating increased thermal stability of CA9 upon ATT-I treatment. To investigate the functional necessity of CA9, AAV9 was employed to silence its expression. In a murine model of DSS-induced colitis, the therapeutic benefits of ATT-I, specifically its capacity to prevent splenic hypertrophy, alleviate leukocyte infiltration, and preserve colonic morphology, were entirely abolished following the genetic knockdown of CA9. Furthermore, the capacity of ATT-I to inhibit ferroptosis in the colon was obviated when CA9 was silenced. For the\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments, silencing CA9 abrogated ATT-I-mediated Claudin-1, Occludin, GPX4 and SLC7A11 upregulation in Erastin-treated Caco-2 cells, indicating that CA9 is an indispensable mediator for ATT-I to restrain Erastin-induced ferroptosis in Caco-2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ATT-I alleviates IBD by modulating ferroptosis mechanisms through targeting CA9. This indicates that ATT-I, as a natural compound, holds potential for regulating ferroptosis, providing a novel therapeutic strategy and approach for IBD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1860254","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T04:25:47Z","timestamp":1785126347000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting carbonic anhydrase IX-mediated ferroptosis by atractylenolide I alleviates DSS-induced colitis in mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqing","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxian","family":"Chen","sequence":"additional","affiliation":[{"name":"The Integrated Traditional Chinese and Western Medicine School of Clinical Medicine, Zhejiang Chinese Medical University","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luzhou","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of Chinese Medicine)","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.pop.2023.03.009","article-title":"Inflammatory bowel disease","volume":"50","author":"Bruner","year":"2023","journal-title":"Prim. 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