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Artesunate (ART), a derivative of Artemisinin, is a widely recognized antimalarial drug that displays notable antitumor properties across diverse cancers. Our previous studies have demonstrated ART\u2019s capacity to inhibit DLBCL progression\n                    <jats:italic>via<\/jats:italic>\n                    the induction of ferroptosis. However, its direct target molecules mediating this effect remained elusive. In this study, using small molecule (SM) pull-down combined with mass spectrometry analysis (LC\u2013MS\/MS), we have identified two peroxidases, PRDX1 and PRDX2, which play key roles in cellular antioxidant processes, as potential target proteins for ART in the treatment of DLBCL cells. Subsequently, we utilized cellular thermal shift assay (CETSA), fluorescence titration, circular dichroism (CD) spectroscopy, molecular docking, and pull-down assays to confirm that ART directly binds to PRDX1 and PRDX2. The Gly4 residue on PRDX1 and the Arg7 and Thr120 residues on PRDX2 are respectively responsible for ART binding. Knockdown of either PRDX1 or PRDX2 not only reproduced the ferroptosis-inducing effect of ART but also significantly attenuated the sensitivity of cells to ART. Furthermore, PRDX2 overexpression attenuated the reactive oxygen species (ROS) production and cytotoxicity in cells treated with ART. Consistently, ART selectively killed DLBCL cells, sparing normal cells thanks to their lower PRDX1 expression. In nude mice bearing U2932 xenografts, ART treatment inhibited significantly tumor growth and improved liver function without causing cardiac or hepatic toxicity, which was associated with an elevated level of ferroptosis and a significantly decreased peroxidase activity. Collectively, our findings elucidate the molecular mechanism by which ART induces ferroptosis through direct interaction with PRDX1 or PRDX2 and highlight these PRDXs as potential therapeutic targets for DLBCL.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07822-7","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T15:06:27Z","timestamp":1752246387000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Artesunate induces ferroptosis in diffuse large B-cell lymphoma cells by targeting PRDX1 and PRDX2"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0625-8195","authenticated-orcid":false,"given":"Xiaohui","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyi","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinman","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiewen","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-4714","authenticated-orcid":false,"given":"Xuejuan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7847-2804","authenticated-orcid":false,"given":"Langxia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"7822_CR1","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1056\/NEJMoa1801445","volume":"378","author":"R Schmitz","year":"2018","unstructured":"Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. 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