{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:41:44Z","timestamp":1784922104518,"version":"3.55.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The sodium-glucose cotransporter (SGLT)2 inhibitor empagliflozin (EMPA) is a hypoglycemic drug for patients with type 2 diabetes mellitus and cardiovascular disease. The mechanisms underlying the beneficial effects of EMPA in counteracting Metabolic Associated Fatty Liver Disease (MAFLD) are poorly understood. Our study aimed to evaluate the therapeutic mechanisms of EMPA treatment (30\u00a0mg\/kg\/day in drinking water for 6\u00a0weeks) on hepatic dysfunction observed in diabetic obese Zucker Diabetic Fatty (ZDF) rats. EMPA activated hepatic insulin signaling, increasing the phosphorylation of insulin receptor, AKT and AMP-activated protein kinase, and downregulated the expression of gluconeogenesis-related genes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase). In the liver of EMPA-treated rats, no difference in SGLT2 and SGLT1 expression was found, while a significant upregulation of GLUT2 protein levels suggested other converging mechanisms on hepatoprotective effects of EMPA. Moreover, EMPA improved hepatic lipid metabolism in ZDF rats, modulating key mediators of fatty acid metabolism and catabolism (cluster of differentiation 36, forkhead box protein O1, fatty acid binding protein 1) and mitochondrial function (uncoupling protein 2 and the mitochondrial transporter ATP-binding cassette 1). Then, we demonstrated EMPA effect against hepatic inflammation and fibrosis, associated with insulin resistance, and, for the first time, its potential as pro-resolving agent increasing immune cell recruitment along with the induction of resolvins (annexin A1 and IL-10). Taken together, our study provides new perspectives for EMPA as a multifaceted approach to counteract MAFLD in obesity and diabetes.<\/jats:p>","DOI":"10.3389\/fphar.2025.1649630","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T04:14:13Z","timestamp":1758600853000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel insights into the hepatoprotective mechanisms of SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats"],"prefix":"10.3389","volume":"16","author":[{"given":"F.","family":"Comella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Arag\u00f3n-Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Melini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Opallo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Feij\u00f3o-Band\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. P.","family":"Navatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Mattace Raso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Gualillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Pirozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Lago-Paz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Meli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19046","DOI":"10.1038\/s41598-023-46288-5","article-title":"Empagliflozin suppresses hedgehog pathway, alleviates ER stress, and ameliorates hepatic fibrosis in rats","volume":"13","author":"Abdalla","year":"2023","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"107023","DOI":"10.1016\/j.intimp.2020.107023","article-title":"Recent insights of the role and signalling pathways of interleukin-34 in liver diseases","volume":"89","author":"Al-Shaebi","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3107","DOI":"10.3390\/ijms23063107","article-title":"SGLT-2 inhibitors in NAFLD: expanding their role beyond diabetes and cardioprotection","volume":"23","author":"Androutsakos","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"113677","DOI":"10.1016\/j.bcp.2019.113677","article-title":"Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of zucker diabetic fatty rats","volume":"170","author":"Aragon-Herrera","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"827033","DOI":"10.3389\/fphar.2022.827033","article-title":"The treatment with the SGLT2 inhibitor empagliflozin modifies the hepatic metabolome of Male zucker diabetic fatty rats towards a protective profile","volume":"13","author":"Aragon-Herrera","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"114535","DOI":"10.1016\/j.biopha.2023.114535","article-title":"The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in zucker diabetic fatty rats","volume":"161","author":"Aragon-Herrera","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1460431","DOI":"10.3389\/fimmu.2024.1460431","article-title":"Identification and validation of efferocytosis-related biomarkers for the diagnosis of metabolic dysfunction-associated steatohepatitis based on bioinformatics analysis and machine learning","volume":"15","author":"Cao","year":"2024","journal-title":"Front. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"E1263","DOI":"10.1210\/jc.2013-4409","article-title":"IL-34 is associated with obesity, chronic inflammation, and insulin resistance","volume":"99","author":"Chang","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2279","DOI":"10.1111\/liv.14940","article-title":"Hepatic macrophages: key players in the development and progression of liver fibrosis","volume":"41","author":"Cheng","year":"2021","journal-title":"Liver Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.jhep.2007.12.017","article-title":"Interleukin-10 is a protective factor against diet-induced insulin resistance in liver","volume":"48","author":"Cintra","year":"2008","journal-title":"J. Hepatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"6498","DOI":"10.3390\/ijms25126498","article-title":"Critical role of mitochondrial fatty acid metabolism in normal cell function and pathological conditions","volume":"25","author":"Dikalov","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3449","DOI":"10.1007\/s00210-023-02826-6","article-title":"Empagliflozin ameliorates liver fibrosis in NASH rat model via targeting hepatic NF-\u03baB\/SOX9\/OPN signaling and osteocalcin level","volume":"397","author":"Elseweidy","year":"2024","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1038\/oby.2008.661","article-title":"Nonalcoholic hepatic steatosis in zucker diabetic rats: spontaneous evolution and effects of metformin and fenofibrate","volume":"17","author":"Forcheron","year":"2009","journal-title":"Obes. (Silver Spring)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1147434","DOI":"10.3389\/fcell.2023.1147434","article-title":"The diverse roles of macrophages in metabolic inflammation and its resolution","volume":"11","author":"Guha Ray","year":"2023","journal-title":"Front. Cell Dev. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"122716","DOI":"10.1016\/j.ijpharm.2023.122716","article-title":"Oral empagliflozin-loaded tri-layer core-sheath fibers fabricated using tri-axial electrospinning: enhanced in vitro and in vivo antidiabetic performance","volume":"635","author":"Guler","year":"2023","journal-title":"Int. J. Pharm."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.2337\/db08-1261","article-title":"Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle","volume":"58","author":"Hong","year":"2009","journal-title":"Diabetes"},{"key":"B18","doi-asserted-by":"publisher","first-page":"eado3141","DOI":"10.1126\/sciadv.ado3141","article-title":"Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis","volume":"10","author":"Hu","year":"2024","journal-title":"Sci. Adv."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e13842","DOI":"10.1111\/1440-1681.13842","article-title":"Empagliflozin attenuates liver fibrosis in high-fat diet\/streptozotocin-induced mice by modulating gut microbiota","volume":"51","author":"Huang","year":"2024","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s13098-016-0169-x","article-title":"Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (A DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes","volume":"8","author":"Jojima","year":"2016","journal-title":"Diabetol. Metab. Syndr."},{"key":"B21","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","article-title":"The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"16","author":"Kazankov","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1111\/bph.15071","article-title":"Palmitoylethanolamide counteracts brain fog improving depressive-like behaviour in obese mice: Possible role of synaptic plasticity and neurogenesis","volume":"178","author":"Lama","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1101\/gad.346312.120","article-title":"Chronic tissue inflammation and metabolic disease","volume":"35","author":"Lee","year":"2021","journal-title":"Genes Dev."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e20190290","DOI":"10.1084\/jem.20190290","article-title":"Emerging roles of IL-34 in health and disease","volume":"217","author":"Lelios","year":"2020","journal-title":"J. Exp. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1002\/hep.27141","article-title":"Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice","volume":"60","author":"Locatelli","year":"2014","journal-title":"Hepatology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"113947","DOI":"10.1016\/j.biopha.2022.113947","article-title":"Empagliflozin reduces kidney fibrosis and improves kidney function by alternative macrophage activation in rats with 5\/6-nephrectomy","volume":"156","author":"Lu","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B27","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.freeradbiomed.2024.01.015","article-title":"Cardiovascular benefits of SGLT2 inhibitors and GLP-1 receptor agonists through effects on mitochondrial function and oxidative stress","volume":"213","author":"Luna-Marco","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"101191","DOI":"10.1016\/j.mam.2023.101191","article-title":"Mechanisms of organ fibrosis: emerging concepts and implications for novel treatment strategies","volume":"92","author":"Lurje","year":"2023","journal-title":"Mol. Asp. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3389\/fendo.2020.00111","article-title":"Liver transcriptomic reveals novel pathways of empagliflozin associated with type 2 diabetic rats","volume":"11","author":"Lv","year":"2020","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B30","doi-asserted-by":"publisher","first-page":"793586","DOI":"10.3389\/fphar.2021.793586","article-title":"Transcriptomic analysis reveals the protective effects of empagliflozin on lipid metabolism in nonalcoholic Fatty liver disease","volume":"12","author":"Ma","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.3390\/ijms22052350","article-title":"Treatments for NAFLD: state of art","volume":"22","author":"Mantovani","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.tips.2018.01.003","article-title":"Specialized proresolving mediators: enhancing nonalcoholic steatohepatitis and fibrosis resolution","volume":"39","author":"Musso","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"818","DOI":"10.3390\/ijms22020818","article-title":"Empagliflozin Attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet Fed ApoE((-\/-)) mice by activating autophagy and reducing ER stress and apoptosis","volume":"22","author":"Nasiri-Ansari","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3606","DOI":"10.1007\/s12325-025-03256-x","article-title":"Metformin: old drug, new therapeutic potential in the skin? A brief narrative review","volume":"42","author":"Pantazopoulos","year":"2025","journal-title":"Adv. Ther."},{"key":"B35","doi-asserted-by":"publisher","first-page":"110539","DOI":"10.1016\/j.mce.2019.110539","article-title":"Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress","volume":"498","author":"Petito-Da-Silva","year":"2019","journal-title":"Mol. Cell Endocrinol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.biopha.2018.04.024","article-title":"Proresolving protein Annexin A1: the role in type 2 diabetes mellitus and obesity","volume":"103","author":"Pietrani","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1143004","DOI":"10.3389\/fnut.2023.1143004","article-title":"Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction by reprogramming microbiota composition and affecting tryptophan metabolism","volume":"10","author":"Pirozzi","year":"2023","journal-title":"Front. Nutr."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.3390\/nano14201642","article-title":"Specialized pro-resolving lipid mediators distinctly modulate silver nanoparticle-induced pulmonary inflammation in healthy and metabolic syndrome mouse models","volume":"14","author":"Pitchai","year":"2024","journal-title":"Nanomater. (Basel)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"4358","DOI":"10.3390\/jcm11154358","article-title":"Macrophages, low-grade inflammation, insulin resistance and hyperinsulinemia: a mutual ambiguous relationship in the development of metabolic diseases","volume":"11","author":"Puschel","year":"2022","journal-title":"J. Clin. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1007\/s00125-022-05851-x","article-title":"Empagliflozin protects mice against diet-induced obesity, insulin resistance and hepatic steatosis","volume":"66","author":"Radlinger","year":"2023","journal-title":"Diabetologia"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1016\/j.jhep.2019.06.031","article-title":"Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease","volume":"71","author":"Rosso","year":"2019","journal-title":"J. Hepatol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/S2213-8587(21)00203-5","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials","volume":"9","author":"Sattar","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.2337\/db24-0405","article-title":"Deficiency of the hemoglobin-haptoglobin receptor, CD163, worsens insulin sensitivity in Obese male mice","volume":"73","author":"Schleh","year":"2024","journal-title":"bioRxiv"},{"key":"B44","doi-asserted-by":"publisher","first-page":"eadh5460","DOI":"10.1126\/scisignal.adh5460","article-title":"Hepatic stellate cells: from bad reputation to mediators of liver homeostasis","volume":"16","author":"Schonberger","year":"2023","journal-title":"Sci. Signal"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mam.2017.08.002","article-title":"New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration","volume":"64","author":"Serhan","year":"2018","journal-title":"Mol. Asp. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3313","DOI":"10.2174\/1381612829666221027112239","article-title":"Empagliflozin exhibits hepatoprotective effects against bile duct ligation-induced liver injury in rats: a combined molecular docking approach to in vivo studies","volume":"28","author":"Shakerinasab","year":"2022","journal-title":"Curr. Pharm. Des."},{"key":"B47","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/978-1-62703-068-7_8","article-title":"Diabetes in zucker diabetic fatty rat","volume":"933","author":"Shiota","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.3390\/ijms21155497","article-title":"Targeting of CD163(+) macrophages in inflammatory and malignant diseases","volume":"21","author":"Skytthe","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"8239258","DOI":"10.1155\/2016\/8239258","article-title":"Annexin A1 and the resolution of inflammation: modulation of neutrophil recruitment, apoptosis, and clearance","volume":"2016","author":"Sugimoto","year":"2016","journal-title":"J. Immunol. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3390\/metabo11020087","article-title":"The effects of SGLT2 inhibitors on lipid metabolism","volume":"11","author":"Szekeres","year":"2021","journal-title":"Metabolites"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1016\/j.jhep.2013.12.025","article-title":"Macrophage heterogeneity in liver injury and fibrosis","volume":"60","author":"Tacke","year":"2014","journal-title":"J. Hepatol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"4697","DOI":"10.1007\/s12325-020-01498-5","article-title":"Effect of empagliflozin on liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease without diabetes: a randomized, double-blind, placebo-controlled trial","volume":"37","author":"Taheri","year":"2020","journal-title":"Adv. Ther."},{"key":"B53","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.molmed.2024.09.005","article-title":"The role of glucose-6-phosphatase activity in glucose homeostasis and its potential for diabetes therapy","volume":"31","author":"Tan","year":"2025","journal-title":"Trends Mol. Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"5408","DOI":"10.4049\/jimmunol.1100225","article-title":"Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype","volume":"187","author":"Titos","year":"2011","journal-title":"J. Immunol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.biomaterials.2016.09.018","article-title":"Anti-obesity and anti-inflammatory effects of macrophage-targeted interleukin-10-conjugated liposomes in Obese mice","volume":"110","author":"Toita","year":"2016","journal-title":"Biomaterials"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1021\/acsptsci.4c00105","article-title":"Hydroxytyrosol linoleoyl ether ameliorates metabolic-associated fatty liver disease symptoms in Obese zucker rats","volume":"7","author":"Tovar","year":"2024","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"531","DOI":"10.2147\/DMSO.S69891","article-title":"Variability in zucker diabetic fatty rats: differences in disease progression in hyperglycemic and normoglycemic animals","volume":"7","author":"Wang","year":"2014","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"B58","doi-asserted-by":"publisher","first-page":"803037","DOI":"10.3389\/fimmu.2021.803037","article-title":"Macrophage polarization and its role in liver disease","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"635556","DOI":"10.3389\/fendo.2021.635556","article-title":"Effect of SGLT2 inhibitors on type 2 diabetes mellitus with non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials","volume":"12","author":"Wei","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B60","doi-asserted-by":"publisher","first-page":"10822","DOI":"10.3390\/ijms221910822","article-title":"Inflammation and oxidative stress in diabetic kidney disease: the targets for SGLT2 inhibitors and GLP-1 receptor agonists","volume":"22","author":"Winiarska","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"836849","DOI":"10.3389\/fphar.2022.836849","article-title":"Emerging roles of sodium glucose cotransporter 2 (SGLT-2) inhibitors in diabetic cardiovascular diseases: focusing on immunity, inflammation and metabolism","volume":"13","author":"Xie","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.ebiom.2017.05.028","article-title":"SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced Obese mice","volume":"20","author":"Xu","year":"2017","journal-title":"EBioMedicine"},{"key":"B63","doi-asserted-by":"publisher","first-page":"e000783","DOI":"10.1136\/bmjdrc-2019-000783","article-title":"Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet","volume":"7","author":"Xu","year":"2019","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"B64","doi-asserted-by":"publisher","first-page":"101257","DOI":"10.1016\/j.molmet.2021.101257","article-title":"Phosphoenolpyruvate carboxykinase in cell metabolism: roles and mechanisms beyond gluconeogenesis","volume":"53","author":"Yu","year":"2021","journal-title":"Mol. Metab."},{"key":"B65","doi-asserted-by":"publisher","first-page":"817542","DOI":"10.3389\/fphys.2022.817542","article-title":"Empagliflozin inhibits hepatic gluconeogenesis and increases glycogen synthesis by AMPK\/CREB\/GSK3\u03b2 signalling pathway","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Physiol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s12933-025-02600-3","article-title":"The protective role of SGLT2 inhibitors on aortic aneurysm mediated by oxidative stress and inflammation in type 2 diabetes mellitus","volume":"24","author":"Zheng","year":"2025","journal-title":"Cardiovasc Diabetol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"600175","DOI":"10.3389\/fphar.2020.600175","article-title":"Liraglutide alleviates hepatic steatosis and liver injury in T2MD rats via a GLP-1R dependent AMPK pathway","volume":"11","author":"Zhou","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1649630\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T04:14:14Z","timestamp":1758600854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1649630\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":69,"alternative-id":["10.3389\/fphar.2025.1649630"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1649630","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,23]]},"article-number":"1649630"}}