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Metformin has been found to have neuroprotective effect, in addition to antidiabetic function. Our recent studies have identified that metformin ameliorates Cd neurotoxicity via blocking ROS-dependent PP5\/AMPK-JNK signaling pathway. Here we further show that metformin protected PC12 cells and primary neurons from Cd-poisoning by mitigating Cd-induced increases in ATG5\/LC3-II\/p62 levels and autophagosomes. Knockdown of ATG5 dramatically potentiated the inhibitory effects of metformin on Cd-induced LC3-II, cleavage of caspase-3, accumulation of autophagosomes and apoptosis in PC12 cells. Addition of chloroquine (CQ) strengthened the basic and Cd-elevated ATG5\/LC3-II\/p62 levels, autophagosome accumulation and cell apoptosis, whereas metformin powerfully blocked the events, implying a metformin-promoted autophagic flux-dependent mechanism involved. Further research revealed that metformin prevented Cd-induced autophagic flux impairment and cell apoptosis, which was attributed to restraining Cd inactivation of AMPK. This is supported by the findings that activation of AMPK with AICAR or ectopic expression of constitutively active AMPK\u03b1 (AMPK\u03b1-ca) reinforced the inhibitory effects of metformin on Cd-evoked ATG5\/LC3-II\/p62\/autophagosomes and apoptosis in PC12 cells and\/or primary neurons. Taken together, the results indicate that metformin protects neuronal cells from Cd-induced autophagic flux impairment-dependent apoptosis by activating AMPK. Our studies highlight that metformin has a great potential for prevention of Cd toxicity related to neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cells15080739","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:38:14Z","timestamp":1776854294000},"page":"739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin Alleviates Cadmium-Induced Autophagic Flux Impairment-Dependent Apoptosis by Activating AMPK in Neuronal Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Wen","family":"Wu","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"},{"name":"Department of Blood Transfusion, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Ji","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyun","family":"Yu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Hou","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoming","family":"Gong","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3239-1072","authenticated-orcid":false,"given":"Shile","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"Department of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2050-8050","authenticated-orcid":false,"given":"Long","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s10072-020-04957-7","article-title":"An overview on amyotrophic lateral sclerosis and cadmium","volume":"42","author":"Oggiano","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1289\/ehp.0901234","article-title":"Cadmium, environmental exposure, and health outcomes","volume":"118","author":"Satarug","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"898034","DOI":"10.1155\/2013\/898034","article-title":"Cadmium and its neurotoxic effects","volume":"2013","author":"Wang","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00128-020-03088-1","article-title":"A review on cadmium exposure in the population and intervention strategies against cadmium toxicity","volume":"106","author":"Wang","year":"2021","journal-title":"Bull. Environ. Contam. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.toxlet.2010.02.019","article-title":"Cadmium in food and human health: Technologies for environmental restoration and rehabilitation January 15\u201317, 2010, Phitsanulok, Thailand","volume":"198","author":"Satarug","year":"2010","journal-title":"Toxicol. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.envres.2017.05.011","article-title":"Cadmium and Alzheimer\u2019s disease mortality in U.S. adults: Updated evidence with a urinary biomarker and extended follow-up time","volume":"157","author":"Peng","year":"2017","journal-title":"Environ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.etap.2006.11.009","article-title":"Cadmium neurotoxicity","volume":"23","author":"Rios","year":"2007","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.biopha.2018.09.054","article-title":"Cadmium nitrate-induced neuronal apoptosis is protected by N-acetyl-l-cysteine via reducing reactive oxygen species generation and mitochondria dysfunction","volume":"108","author":"Lee","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"125198","DOI":"10.1016\/j.jhazmat.2021.125198","article-title":"Cadmium-induced dysfunction of the blood-brain barrier depends on ROS-mediated inhibition of PTPase activity in zebrafish","volume":"412","author":"Zhang","year":"2021","journal-title":"J. Hazard. Mater."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1080\/01616412.2019.1596206","article-title":"Rutin hydrate inhibits apoptosis in the brains of cadmium chloride-treated rats via preserving the mitochondrial integrity and inhibiting endoplasmic reticulum stress","volume":"41","author":"Mostafa","year":"2019","journal-title":"Neurol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/0006-8993(79)90143-4","article-title":"Inhibition of striatal muscarinic receptors in vivo by cadmium","volume":"168","author":"Hedlund","year":"1979","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105144","DOI":"10.1016\/j.neuint.2021.105144","article-title":"Cadmium promotes glycolysis upregulation and glutamine dependency in human neuronal cells","volume":"149","author":"Bovio","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.freeradbiomed.2010.12.032","article-title":"Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death","volume":"50","author":"Chen","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1093\/toxsci\/kfm106","article-title":"Cadmium-induced toxicity in rat primary mid-brain neuroglia cultures: Role of oxidative stress from microglia","volume":"98","author":"Yang","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1089\/ars.2013.5371","article-title":"An overview of autophagy: Morphology, mechanism, and regulation","volume":"20","author":"Parzych","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and molecular mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.2174\/0929867325666180226094351","article-title":"Role of autophagy in Parkinson\u2019s disease","volume":"26","author":"Cerri","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/s41418-019-0480-9","article-title":"Autophagy and disease: Unanswered questions","volume":"27","author":"Yang","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/nm.3232","article-title":"The role of autophagy in neurodegenerative disease","volume":"19","author":"Nixon","year":"2013","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/978-981-15-4272-5_3","article-title":"Autophagy and motor neuron diseases","volume":"1207","author":"Zhang","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1146\/annurev-cellbio-100818-125242","article-title":"Autophagy in neurons","volume":"35","author":"Stavoe","year":"2019","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1080\/15548627.2020.1840796","article-title":"Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons","volume":"17","author":"Zhang","year":"2012","journal-title":"Autophagy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/978-1-4939-2522-3_10","article-title":"Measuring autophagy in stressed cells","volume":"1292","author":"Sharifi","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"188","DOI":"10.4161\/auto.7.2.14181","article-title":"Dissecting the dynamic turnover of GFP-LC3 in the autolysosome","volume":"7","author":"Ni","year":"2011","journal-title":"Autophagy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","article-title":"LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing","volume":"19","author":"Kabeya","year":"2000","journal-title":"EMBO J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1038\/ncb3256","article-title":"Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming","volume":"17","author":"Ma","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16753","DOI":"10.1074\/jbc.M115.708081","article-title":"RACK1 Is an Interaction Partner of ATG5 and a Novel Regulator of Autophagy","volume":"291","author":"Erbil","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/nature03029","article-title":"The role of autophagy during the early neonatal starvation period","volume":"432","author":"Kuma","year":"2004","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1038\/cdd.2013.104","article-title":"p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene","volume":"20","author":"He","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/nature07976","article-title":"Autophagy regulates lipid metabolism","volume":"458","author":"Singh","year":"2009","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.cellsig.2018.12.008","article-title":"Cadmium results in accumulation of autophagosomes-dependent apoptosis through activating Akt-impaired autophagic flux in neuronal cells","volume":"55","author":"Zhang","year":"2019","journal-title":"Cell. Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/jnc.13562","article-title":"Metformin-induced mitochondrial function and ABCD2 up-regulation in X-linked adrenoleukodystrophy involves AMP-activated protein kinase","volume":"138","author":"Singh","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21830","DOI":"10.1073\/pnas.0912793107","article-title":"Biguanide metformin acts on tau phosphorylation via mTOR\/protein phosphatase 2A (PP2A) signaling","volume":"107","author":"Kickstein","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neulet.2006.10.039","article-title":"Metformin therapy in a transgenic mouse model of Huntington\u2019s disease","volume":"411","author":"Ma","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1152\/physrev.00011.2008","article-title":"AMPK in health and disease","volume":"89","author":"Steinberg","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cmet.2014.03.002","article-title":"AMPK at the nexus of energetics and aging","volume":"20","author":"Burkewitz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cmet.2016.09.003","article-title":"Metformin activates AMPK through the lysosomal pathway","volume":"24","author":"Zhang","year":"2016","journal-title":"Cell Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/nm.3372","article-title":"Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin","volume":"19","author":"Fullerton","year":"2013","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41586-022-04431-8","article-title":"Low-dose metformin targets the lysosomal AMPK pathway through PEN2","volume":"603","author":"Ma","year":"2022","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"110628","DOI":"10.1016\/j.mce.2019.110628","article-title":"Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK\/SIRT1-FoxO1 pathway","volume":"500","author":"Ren","year":"2020","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, S.X., Li, C., Pang, X.R., Zhang, J., Yu, G.C., Yeo, A.J., Lavin, M.F., Shao, H., Jia, Q., and Peng, C. (2021). Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.719589"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"108065","DOI":"10.1016\/j.neuropharm.2020.108065","article-title":"Metformin attenuates cadmium-induced neuronal apoptosis in vitro via blocking ROS-dependent PP5\/AMPK-JNK signaling pathway","volume":"175","author":"Chen","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.biocel.2008.10.029","article-title":"Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway","volume":"41","author":"Chen","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"47898","DOI":"10.1074\/jbc.M408149200","article-title":"AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells","volume":"279","author":"Zang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.freeradbiomed.2008.07.011","article-title":"Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5","volume":"45","author":"Chen","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"115139","DOI":"10.1016\/j.bcp.2022.115139","article-title":"Resveratrol induces autophagy impeding BAFF-stimulated B-cell proliferation and survival by inhibiting the Akt\/mTOR pathway","volume":"202","author":"Yao","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1128\/AAC.01366-12","article-title":"Caspofungin kills Candida albicans by causing both cellular apoptosis and necrosis","volume":"57","author":"Hao","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_49","first-page":"3","article-title":"Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles","volume":"66","author":"Biederbick","year":"1995","journal-title":"Eur. J. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.arr.2016.08.008","article-title":"ER stress and impaired autophagy flux in neuronal degeneration and brain injury","volume":"34","author":"Yin","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e1179","DOI":"10.1038\/cddis.2014.162","article-title":"Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD","volume":"5","author":"Mayoral","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Yi, H., Wang, K., Du, B., He, L., Ho, H., Qiu, M., Zou, Y., Li, Q., Jin, J., and Zhan, Y. (2018). Aleuritolic acid impaired autophagic flux and induced apoptosis in hepatocellular carcinoma HepG2 cells. Molecules, 23.","DOI":"10.3390\/molecules23061338"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Islam, M.A., Sooro, M.A., and Zhang, P. (2018). Autophagic regulation of p62 is critical for cancer therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051405"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kumar, A.V., Mills, J., and Lapierre, L.R. (2022). Selective autophagy receptor p62\/SQSTM1, a pivotal player in stress and aging. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.793328"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/toxsci\/kfad045","article-title":"Cadmium-induced stress: A close look at the relationship between autophagy and apoptosis","volume":"194","author":"Tuffour","year":"2023","journal-title":"Toxicol. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-981-15-0602-4_4","article-title":"AMPK and Autophagy","volume":"1206","author":"Li","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"16619","DOI":"10.1002\/jcp.28337","article-title":"Metformin protects PC12 cells and hippocampal neurons from H2O2-induced oxidative damage through activation of AMPK pathway","volume":"234","author":"Zhao","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1096\/fj.10-167361","article-title":"Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation","volume":"25","author":"Vingtdeux","year":"2011","journal-title":"FASEB J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s10534-010-9288-2","article-title":"Early biomarkers of cadmium exposure and nephrotoxicity","volume":"23","author":"Prozialeck","year":"2010","journal-title":"Biometals"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40618-019-01060-3","article-title":"Metformin as a protective agent against natural or chemical toxicities: A comprehensive review on drug repositioning","volume":"43","author":"Meshkani","year":"2020","journal-title":"J. Endocrinol. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/S1474-4422(13)70278-3","article-title":"Neurobehavioural effects of developmental toxicity","volume":"13","author":"Grandjean","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.taap.2011.05.001","article-title":"Oxidative stress in MeHg-induced neurotoxicity","volume":"256","author":"Farina","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00204-014-1425-1","article-title":"Role of autophagy in methylmercury-induced neurotoxicity in rat primary astrocytes","volume":"90","author":"Yuntao","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.cmet.2017.10.009","article-title":"AMPK: Sensing glucose as well as cellular energy status","volume":"27","author":"Lin","year":"2018","journal-title":"Cell Metab."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/8\/739\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:16:40Z","timestamp":1777090600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/8\/739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":66,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cells15080739"],"URL":"https:\/\/doi.org\/10.3390\/cells15080739","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]}}}