{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T02:40:25Z","timestamp":1784860825557,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,10,13]],"date-time":"2024-10-13T00:00:00Z","timestamp":1728777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int J Experimental Path"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although single treatment with sodium\u2010glucose cotransporter\u20102 inhibitors (SGLT2i) or vitamin D<jats:sub>3<\/jats:sub> (VD<jats:sub>3<\/jats:sub>) inhibited metabolic dysfunction\u2010associated steatohepatitis (MASH) development in diabetic patients, their combination has\u00a0not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and\/or VD<jats:sub>3<\/jats:sub> against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD<jats:sub>3<\/jats:sub>, and SGLT2i\u2009+\u2009VD<jats:sub>3<\/jats:sub> groups. All animals, except the NC group, received high\u2010fructose\/high\u2010fat diet (8\u2009weeks) followed by diabetes induction. Diabetic mice then received another cycle of high\u2010fructose\/high\u2010fat diet (4\u2009weeks) followed by 8\u2009weeks of treatment (five times\/week) with SGLT2i (5.1\u2009mg\/kg\/day) and\/or VD<jats:sub>3<\/jats:sub> (410\u2009IU\/Kg\/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non\u2010alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP\u20101\/PPAR\u03b3), oxidative stress (MDA\/H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>), inflammation (IL1\u03b2\/IL6\/TNF\u2010\u03b1), fibrosis (TGF\u2010\u03b21\/\u03b1\u2010SMA), and apoptosis (TUNEL\/Caspase\u20103) markers alongside the PI3K\/AKT\/mTOR pathway increased in the PC group. Conversely, hepatic insulin\u2010dependent glucose transporter (GLUT4), lipolytic (PPAR\u03b1\/INSIG1), antioxidant (GSH\/GPx1\/SOD1\/CAT), and anti\u2010inflammatory (IL\u201010) molecules with the inhibitor of PI3K\/AKT\/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD<jats:sub>3<\/jats:sub>, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose\u2010transporting and lipid\u2010regulatory molecules, PI3K\/AKT\/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD<jats:sub>3<\/jats:sub> co\u2010therapy against diabetes\u2010induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K\/AKT\/mTOR, anti\u2010inflammatory, anti\u2010oxidative, and anti\u2010fibrotic pathways.<\/jats:p>","DOI":"10.1111\/iep.12519","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T03:50:08Z","timestamp":1728877808000},"page":"219-234","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction\u2010associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways"],"prefix":"10.1111","volume":"105","author":[{"given":"Wesam F.","family":"Farrash","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences Umm Al\u2010Qura University  Makkah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakir","family":"Idris","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences Umm Al\u2010Qura University  Makkah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed E.","family":"Elzubier","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine Umm Al\u2010Qura University  Makkah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elshiekh B. 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