{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:02:41Z","timestamp":1789095761849,"version":"build-2803163510"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Science and Technology Project","award":["JCYJ20220531092405011"],"award-info":[{"award-number":["JCYJ20220531092405011"]}]},{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzhen","doi-asserted-by":"crossref","award":["SZZYSM202311004"],"award-info":[{"award-number":["SZZYSM202311004"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Type 1 diabetes mellitus (T1DM) is characterized by autoimmune-mediated destruction of pancreatic islet \u03b2-cells and the resultant absolute insulin deficiency, which leads to systemic metabolic dysregulation. Hepatic injury has emerged as a clinically significant complication of T1DM; however, no targeted therapeutic intervention is currently available. Artemether (Art), a methyl ether derivative of artemisinin, has shown potential in ameliorating hyperglycemia, but its efficacy in mitigating T1DM-associated hepatic dysfunction remains insufficiently elucidated. This study comprehensively evaluates the hepatoprotective effects of Art in a murine model of T1DM, with particular emphasis on mitochondrial structural integrity and the regulation of glucose and lipid metabolism. Hepatic function was assessed through histopathological evaluation, ultrastructural examination of mitochondria via transmission electron microscopy, and molecular analysis of gene and protein expression levels. Metabolic intermediates associated with glucose and lipid metabolic pathways were quantitatively analyzed using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UPLC-QQQ-MS\/MS). Administration of Art significantly attenuated both diabetic manifestations and liver injury. Importantly, Art preserved mitochondrial morphology, restored the expression of some proteins related to the respiratory chain complex, and downregulated indicators of hepatic fatty acid \u03b2-oxidation, upregulated markers of de novo fatty acid synthesis, normalized intrahepatic triglyceride concentrations, and reduced expression of key molecules involved in gluconeogenesis and glycogenolysis. These findings indicate that Art confers protective effects against liver injury in T1DM through coordinated modulation of mitochondrial function and key metabolic pathways at transcriptional, translational, and metabolic intermediate levels.<\/jats:p>","DOI":"10.1371\/journal.pone.0348214","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:44:03Z","timestamp":1777484643000},"page":"e0348214","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Artemether ameliorates type 1 diabetic liver injury alongside the associated defects in mitochondrial ultrastructure and central carbon metabolism"],"prefix":"10.1371","volume":"21","author":[{"given":"Qike","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufen","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengxun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mumin","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huili","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9294-8738","authenticated-orcid":true,"given":"Yuchun","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"issue":"10","key":"pone.0348214.ref001","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/S2213-8587(22)00218-2","article-title":"Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: A modelling study","volume":"10","author":"GA Gregory","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"18","key":"pone.0348214.ref002","article-title":"Emerging targets in Type 2 diabetes and diabetic complications","volume":"8","author":"S Demir","year":"2021","journal-title":"Adv Sci (Weinh)"},{"key":"pone.0348214.ref003","doi-asserted-by":"crossref","first-page":"115737","DOI":"10.1016\/j.biopha.2023.115737","article-title":"Fibroblast growth factor 21 protects the liver from apoptosis in a type 1 diabetes mouse model via regulating L-lactate homeostasis","volume":"168","author":"J Yan","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"pone.0348214.ref004","article-title":"Global epidemiology and characteristics of metabolic dysfunction-associated steatotic liver disease in type 1 diabetes mellitus: An updated systematic review and meta-analysis","author":"M Souza","year":"2024","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"2","key":"pone.0348214.ref005","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.apsb.2020.09.001","article-title":"Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics","volume":"11","author":"D Dolivo","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"pone.0348214.ref006","doi-asserted-by":"crossref","first-page":"435713","DOI":"10.1155\/2015\/435713","article-title":"Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives","volume":"2015","author":"C Shi","year":"2015","journal-title":"Mediators Inflamm"},{"issue":"1","key":"pone.0348214.ref007","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/1753-0407.13347","article-title":"Artemether treatment improves islet function and metabolic homeostasis in diabetic nonhuman primates","volume":"15","author":"W Fu","year":"2023","journal-title":"J Diabetes"},{"key":"pone.0348214.ref008","first-page":"8639523","article-title":"Antidiabetic and antiobesity effects of artemether in db\/db Mice","volume":"2018","author":"Y Guo","year":"2018","journal-title":"Biomed Res Int"},{"issue":"6","key":"pone.0348214.ref009","first-page":"3879","article-title":"Artemether improves type 1 diabetic kidney disease by regulating mitochondrial function","volume":"11","author":"Y Wang","year":"2019","journal-title":"Am J Transl Res"},{"issue":"1","key":"pone.0348214.ref010","doi-asserted-by":"crossref","first-page":"27","DOI":"10.62347\/NEAS4467","article-title":"Artemether regulates liver glycogen and lipid utilization through mitochondrial pyruvate oxidation in db\/db mice","volume":"16","author":"W Weng","year":"2024","journal-title":"Am J Transl Res"},{"issue":"3","key":"pone.0348214.ref011","first-page":"1389","article-title":"Artemether ameliorates type 2 diabetic kidney disease by increasing mitochondrial pyruvate carrier content in db\/db mice","volume":"11","author":"P Han","year":"2019","journal-title":"Am J Transl Res"},{"issue":"3","key":"pone.0348214.ref012","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3892\/etm.2022.11164","article-title":"Combined treatment with niclosamide ethanolamine and artemether combination improves type 1 diabetes via the targeting of liver mitochondria","volume":"23","author":"W Weng","year":"2022","journal-title":"Exp Ther Med"},{"issue":"2","key":"pone.0348214.ref013","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jhep.2025.02.033","article-title":"Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms","volume":"83","author":"GR Steinberg","year":"2025","journal-title":"J Hepatol"},{"issue":"2","key":"pone.0348214.ref014","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.tem.2024.07.010","article-title":"Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases","volume":"36","author":"A Nasuhidehnavi","year":"2025","journal-title":"Trends Endocrinol Metab"},{"key":"pone.0348214.ref015","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.mito.2014.09.002","article-title":"ATP\/ADP ratio, the missed connection between mitochondria and the Warburg effect","author":"EN Maldonado","year":"2014","journal-title":"Mitochondrion"},{"issue":"10","key":"pone.0348214.ref016","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.tem.2024.05.005","article-title":"Is mitochondrial morphology important for cellular physiology?","volume":"35","author":"T Wai","year":"2024","journal-title":"Trends Endocrinol Metab"},{"issue":"2","key":"pone.0348214.ref017","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1083\/jcb.30.2.269","article-title":"Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria","volume":"30","author":"CR Hackenbrock","year":"1966","journal-title":"J Cell Biol"},{"key":"pone.0348214.ref018","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.mito.2021.06.008","article-title":"Chronic treatment with dapagliflozin protects against mitochondrial dysfunction in the liver of C57BL\/6NCrl mice with high-fat diet\/streptozotocin-induced diabetes mellitus","volume":"59","author":"KN Belosludtsev","year":"2021","journal-title":"Mitochondrion"},{"issue":"5","key":"pone.0348214.ref019","doi-asserted-by":"crossref","DOI":"10.1016\/j.molcel.2019.03.031","article-title":"ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2\u03b1 Axis","volume":"74","author":"E Balsa","year":"2019","journal-title":"Mol Cell"},{"key":"pone.0348214.ref020","doi-asserted-by":"crossref","first-page":"107409","DOI":"10.1016\/j.phrs.2024.107409","article-title":"A new perspective on liver diseases: Focusing on the mitochondria-associated endoplasmic reticulum membranes","volume":"208","author":"M Guo","year":"2024","journal-title":"Pharmacol Res"},{"issue":"6008","key":"pone.0348214.ref021","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1126\/science.1189157","article-title":"PML regulates apoptosis at endoplasmic reticulum by modulating calcium release","volume":"330","author":"C Giorgi","year":"2010","journal-title":"Science"},{"issue":"10","key":"pone.0348214.ref022","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.3390\/nu15102323","article-title":"Dysregulation of lipid and glucose metabolism in nonalcoholic fatty liver disease","volume":"15","author":"N Bhat","year":"2023","journal-title":"Nutrients"},{"key":"pone.0348214.ref023","doi-asserted-by":"crossref","first-page":"710420","DOI":"10.3389\/fphys.2021.710420","article-title":"Metabolic Changes of Hepatocytes in NAFLD","volume":"12","author":"Q Lu","year":"2021","journal-title":"Front Physiol"},{"issue":"3","key":"pone.0348214.ref024","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1089\/ars.2012.4910","article-title":"Mitochondrial plasticity in obesity and diabetes mellitus","volume":"19","author":"T Jelenik","year":"2013","journal-title":"Antioxid Redox Signal"},{"key":"pone.0348214.ref025","doi-asserted-by":"crossref","first-page":"104714","DOI":"10.1016\/j.ebiom.2023.104714","article-title":"Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases","volume":"94","author":"B Dewidar","year":"2023","journal-title":"EBioMedicine"},{"issue":"7","key":"pone.0348214.ref026","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nm.3629","article-title":"Absence of leptin triggers type 1 diabetes","volume":"20","author":"B Mittendorfer","year":"2014","journal-title":"Nat Med"},{"issue":"8","key":"pone.0348214.ref027","doi-asserted-by":"crossref","first-page":"5794","DOI":"10.1111\/jcmm.14504","article-title":"Hepatic functional and pathological changes of type 1 diabetic mice in growing and maturation time","volume":"23","author":"S Jiang","year":"2019","journal-title":"J Cell Mol Med"},{"issue":"2","key":"pone.0348214.ref028","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3892\/mmr.2020.11175","article-title":"Diabetic\u2011induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review)","volume":"22","author":"S Jiang","year":"2020","journal-title":"Mol Med Rep"},{"issue":"19","key":"pone.0348214.ref029","doi-asserted-by":"crossref","first-page":"11268","DOI":"10.1074\/jbc.271.19.11268","article-title":"Suppression of glycolysis is associated with an increase in glucose cycling in hepatocytes from diabetic rats","volume":"271","author":"DC Henly","year":"1996","journal-title":"J Biol Chem"},{"issue":"2","key":"pone.0348214.ref030","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1172\/JCI116226","article-title":"Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus","volume":"91","author":"S Del Prato","year":"1993","journal-title":"J Clin Invest"},{"issue":"7","key":"pone.0348214.ref031","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1017\/S0007114511006635","article-title":"Beneficial effects of ginger (Zingiber officinale) on carbohydrate metabolism in streptozotocin-induced diabetic rats","volume":"108","author":"NB Abdulrazaq","year":"2012","journal-title":"Br J Nutr"},{"issue":"12","key":"pone.0348214.ref032","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.2337\/diabetes.49.12.2063","article-title":"Mechanism by which metformin reduces glucose production in type 2 diabetes","volume":"49","author":"RS Hundal","year":"2000","journal-title":"Diabetes"},{"key":"pone.0348214.ref033","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.mam.2015.09.003","article-title":"Molecular pathophysiology of hepatic glucose production","volume":"46","author":"K Sharabi","year":"2015","journal-title":"Mol Aspects Med"},{"issue":"4","key":"pone.0348214.ref034","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1172\/JCI115997","article-title":"Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study","volume":"90","author":"I Magnusson","year":"1992","journal-title":"J Clin Invest"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348214","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:44:11Z","timestamp":1777484651000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0348214"}},"subtitle":[],"editor":[{"given":"Xiaosheng","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0348214","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]}}}