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In this study, we developed a multi\u2010functional nanoregulator (HCoMB) based on high\u2010density Co single\u2010atom nanozyme (HCoN\n                    <jats:sub>4<\/jats:sub>\n                    ) for efficient inhibition of MIRI pathological progression, potentially through disruption of the cycle of \u201coxidative stress\u2010ferroptosis\u2010inflammatory response\u201d. HCoN\n                    <jats:sub>4<\/jats:sub>\n                    with 11.05\u00a0wt% Co loading exhibited boosted glutathione peroxidase (GPx)\u2010like activity, superoxide dismutase (SOD)\u2010like and catalase (CAT)\u2010like catalytic activities due to the increased metal loading, which not only raised the number of catalytic active centers but also effectively improved the intrinsic activity of individual sites via electron transfer between densely distributed active sites. It can efficiently and stably scavenge ROS, upregulate the expression of glutathione peroxidase 4 (GPx4), and block the core pathway of ferroptosis. In addition, the combination with ML355 could specifically block the p53\u2010mediated ferroptosis process by inhibiting ALOX12 activity. Mechanistically, the synergistic effect can significantly alleviate lipid peroxidation and oxidative stress injury in cardiomyocytes, and ultimately break the vicious cascade cycle of oxidative stress, ferroptosis and inflammatory response, and realize effective protection against MIRI.\n                  <\/jats:p>","DOI":"10.1002\/anie.3395960","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:34:47Z","timestamp":1786725287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["High\u2010Density Co\u2010Based Single\u2010Atom Nanozymes Alleviate Myocardial Ischemia\u2010Reperfusion Injury by Disrupting the Cycle of Oxidative Stress\u2010Ferroptosis\u2010Inflammatory Response"],"prefix":"10.1002","volume":"65","author":[{"given":"Bin","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Rare Earths Chinese Academy of Sciences Changchun Institute of Applied Chemistry Chinese Academy of Sciences  Changchun Jilin P. 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