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Here, we identify an AMP\u2010activated protein kinase (AMPK)\u2013mitochondrial reactive oxygen species (mtROS)\u2013RIPK1\/RIPK3\u2013MLKL axis as a central driver of Cd neurotoxicity and a critical target of metformin. In a chronic Cd\u2010exposed mouse model and in primary hippocampal neurons, Cd provoked prominent neuronal injury characterized by the activation of necroptotic signaling (elevated p\u2010RIPK1, p\u2010RIPK3, and p\u2010MLKL), excessive mtROS production, and mitochondrial injury. Oral metformin preserved hippocampal neuronal integrity and suppressed necroptotic markers in\u00a0vivo, while in cultured neurons and SH\u2010SY5Y cells, it reduced mtROS, maintained mitochondrial morphology and membrane potential, and prevented necrosome assembly. Pharmacologic inhibition of RIPK1 (necrostatin\u20101) or RIPK3 (GSK\u2010872), as well as CRISPR\/Cas9\u2010mediated deletion of RIPK1, RIPK3, or MLKL, attenuated Cd\u2010induced necrosis and phenocopied or enhanced the anti\u2010necroptotic effects of metformin. Mechanistically, metformin restored Cd\u2010suppressed AMPK activity, whereas blockade of AMPK with compound C or expression of a dominant\u2010negative AMPK\u03b11 mutant abolished metformin\u2010mediated suppression of mtROS, RIPK1\/RIPK3\u2013MLKL signaling, and necroptosis. Scavenging mtROS with Mito\u2010TEMPO or MitoQ reduced necroptosis and synergized with metformin to disrupt RIPK3\u2013MLKL complex formation. Collectively, these findings demonstrate that Cd triggers neuronal necroptosis via mtROS\u2010driven activation of RIPK1\/RIPK3\u2013MLKL, and that metformin confers neuroprotection by activating AMPK to restore mitochondrial homeostasis and restrain necroptotic signaling. This work positions the AMPK\u2013mtROS\u2013necroptosis axis as a therapeutically actionable pathway in heavy\u2010metal neurotoxicity and supports repurposing metformin for necroptosis\u2010associated neurodegenerative conditions.<\/jats:p>","DOI":"10.1096\/fj.202504635r","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T15:23:30Z","timestamp":1771601010000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Metformin Activates\n                    <scp>AMPK<\/scp>\n                    to Restrain Mitochondrial\n                    <scp>ROS<\/scp>\n                    \u2010Driven Necroptosis in Cadmium Neurotoxicity"],"prefix":"10.1096","volume":"40","author":[{"given":"Xiaoling","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Blood Transfusion, the First Affiliated Hospital of Wannan Medical College  Wuhu China"},{"name":"School of Basic Medical Science and Clinical Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science and Clinical Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion, the First Affiliated Hospital of Wannan Medical College  Wuhu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science and Clinical Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongsheng","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Blood Transfusion, the First Affiliated Hospital of Wannan Medical College  Wuhu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2228-9063","authenticated-orcid":false,"given":"Chong","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Science and Clinical Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202402030"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-8467(97)00090-5"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/898034"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0093-1"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/35037739"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916427117"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.05133.x"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22565"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-052016-100247"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12964"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305432"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-020-00370-3"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14329"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.01.030"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.070"},{"key":"e_1_2_14_17_1","first-page":"319","article-title":"Metformin Inhibits ROS Production by Human M2 Macrophages via the Activation of AMPK","volume":"10","author":"Nassif R. 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