{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:21:32Z","timestamp":1793262092471,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Icaritin (ICT) is a natural isoprenylated flavonoid compound extracted from the traditional Chinese herbal medicine\n                      <jats:italic>Epimedii Folium<\/jats:italic>\n                      . Metallothioneins (MTs) are a group of low-molecular-weight, cysteine-rich proteins that play crucial roles in oxidative stress, metal homeostasis, and cancer drug resistance. The anticancer effect and detailed regulatory mechanism of ICT in breast cancer remain to be fully clarified. This study aims to investigate the anti-tumor activity of ICT in breast cancer and explore its underlying molecular mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      assays were performed in breast cancer cell lines to evaluate cell viability, intracellular Fe\n                      <jats:sup>2+<\/jats:sup>\n                      levels, reactive oxygen species (ROS) production, and protein expression of the ferroptosis-associated antioxidant molecules SLC7A11 and GPX4 following ICT treatment. A ferroptosis inhibitor was employed to confirm the causal role of ferroptosis in ICT\u2019s efficacy. Key target genes regulated by ICT were screened via transcriptome sequencing, and functional validation was conducted through MT1X overexpression to assess its impacts on NF-\u03baB pathway activation, cell cycle distribution, and the SLC7A11\/GPX4 axis. A breast cancer xenograft mouse model was established to verify the in vivo anti-tumor effect and mechanism of ICT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ICT induced ferroptosis and suppressed viability in breast cancer cells, as evidenced by intracellular Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation, elevated ROS levels, and downregulated SLC7A11 and GPX4. This anti-tumor effect was reversed by a ferroptosis inhibitor, confirming ferroptosis as the key mechanism of ICT. Transcriptomic analysis and functional validation showed that ICT markedly upregulated MT1X. MT1X overexpression inhibited NF-\u03baB signaling via reducing I\u03baB\u03b1 and p65 phosphorylation, induced G1 cell cycle arrest, and suppressed the SLC7A11\/GPX4 antioxidant axis, synergistically enhancing ICT\u2019s anti-proliferative activity.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , ICT-mediated MT1X upregulation promoted ferroptosis and inhibited tumor growth.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study elucidates that ICT exerts anti-breast cancer effects by activating MT1X to induce ferroptosis and cooperatively inhibit the NF-\u03baB signaling pathway. Our findings reveal a novel molecular mechanism of ICT against breast cancer, and provide a new therapeutic target and experimental basis for breast cancer treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1868122","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:24:34Z","timestamp":1783657474000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Icaritin inhibits breast cancer through activating MT1X to promote ferroptosis and synergizing with NF-\u03baB pathway suppression"],"prefix":"10.3389","volume":"16","author":[{"given":"Fenglin","family":"Zhan","sequence":"first","affiliation":[{"name":"Wuxi School of Medicine, Jiangnan University","place":["Wuxi, China"]},{"name":"Department of Nuclear Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of 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