{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:15:08Z","timestamp":1788362108838,"version":"build-2803163510"},"reference-count":100,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012899","name":"Lanzhou University Education Development Foundation","doi-asserted-by":"publisher","award":["CY2025-MS-B10"],"award-info":[{"award-number":["CY2025-MS-B10"]}],"id":[{"id":"10.13039\/100012899","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The discovery of ferroptosis and cuproptosis has significantly expanded the landscape of programmed cell death. Artesunate (ART), a semisynthetic derivative of artemisinin, exhibits pleiotropic pharmacological activities beyond its canonical antimalarial role, including anticancer and neuroprotective effects. However, a comprehensive review systematically integrating ART\u2019s roles in modulating both ferroptosis and cuproptosis remains lacking. This review bridges this gap by synthesizing recent advances. The distinct core mechanisms of ferroptosis and cuproptosis are first outlined. Extensive evidence is then summarized regarding ART-induced ferroptosis in cancers, primarily through disrupting iron homeostasis (e.g., stabilizing transferrin receptor (TFRC), promoting ferritinophagy) and impairing antioxidant defenses (e.g., suppressing the System Xc\u2212\/ glutathione peroxidase 4 (GPX4) axis, targeting peroxiredoxins). In contrast, the anti-cuproptotic effect of ART is currently restricted to Parkinson\u2019s disease (PD) models, mediated by the upregulation of astrocytic metallothionein 2A (MT2A) to chelate excess copper\u2014the only validated cuproptosis-related mechanism of ART to date. The crosstalk between ferroptosis and cuproptosis at shared metabolic nodes, including glutathione depletion, mitochondrial dysfunction, and reactive oxygen species (ROS) amplification, is further delineated as a hypothesis-generating framework. This interplay suggests a theoretical potential for ART\u2014when combined with functional nano-materials\u2014to synchronously engage both death pathways, though direct experimental validation of such dual-pathway synergy for ART as a single agent remains lacking. Finally, translational prospects of ART in cancer therapy, neurodegenerative diseases, and hepatic fibrosis are discussed, together with current challenges and future directions. ART acts as a context-dependent modulator: pro-ferroptotic activity is evident across multiple disease models, whereas anti-cuproptotic activity is currently limited to PD and requires further validation. Systematic characterization of ART\u2019s context-specific effects suggests a preclinical rationale for the future design of ART-based combination strategies targeting metal-dependent cell death, pending further validation.<\/jats:p>","DOI":"10.3390\/ijms27177862","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T14:35:29Z","timestamp":1788359729000},"page":"7862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Artesunate in Ferroptosis and Cuproptosis Regulation: Context-Dependent Mechanisms, Interplay, and Therapeutic Implications"],"prefix":"10.3390","volume":"27","author":[{"given":"Kai","family":"Feng","sequence":"first","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayi","family":"Xia","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsheng","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1490-1787","authenticated-orcid":false,"given":"Mingxuan","family":"Yang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1093\/procel\/pwae003","article-title":"Metabolic Cell Death in Cancer: Ferroptosis, Cuproptosis, Disulfidptosis, and Beyond","volume":"15","author":"Mao","year":"2024","journal-title":"Protein Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/15548627.2022.2059170","article-title":"Identification of HPCAL1 as a Specific Autophagy Receptor Involved in Ferroptosis","volume":"19","author":"Chen","year":"2023","journal-title":"Autophagy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1016\/j.cell.2023.05.003","article-title":"Ferroptosis Surveillance Independent of GPX4 and Differentially Regulated by Sex Hormones","volume":"186","author":"Liang","year":"2023","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/s41556-023-01133-9","article-title":"Creatine Kinase B Suppresses Ferroptosis by Phosphorylating GPX4 through a Moonlighting Function","volume":"25","author":"Wu","year":"2023","journal-title":"Nat. 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