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Aging is a major risk factor for the development and progression of MASLD. In this study, we investigated the metabolic effects of tilorone, a synthetic small molecule, in a high-fat diet (HFD) mouse model, with a focus on the liver function and signaling. We demonstrate that tilorone attenuated HFD-induced steatosis by restoring bone morphogenetic protein 9 (BMP9)-Smad1\/5\/8 signaling and upregulating peroxisome proliferator-activated receptor gamma (PPAR\u03b3) expression. Tilorone reduced HFD-induced increases in body weight, adipose tissue and liver weight, and blood glucose levels, and improved glucose tolerance in HFD mice. PET\/MRI imaging demonstrated enhanced\n                    <jats:sup>18<\/jats:sup>\n                    FDG (\n                    <jats:sup>18<\/jats:sup>\n                    F-fluoro-2-deoxyglucose) uptake in liver, skeletal muscle, adipose tissue, and myocardium of tilorone-treated HFD animals. Histological analysis showed that tilorone reduced the HFD-induced diffuse, macrovesicular steatosis (S3\/3), and machine learning-based image analysis revealed a decrease in lipid droplet size and lipid content. HFD caused the disappearance of liver glycogen, but tilorone increased glycogen levels. High-resolution respirometry indicated that tilorone reduced HFD-induced increases in mitochondrial complex II-linked oxidative phosphorylation and complex IV activity. These findings revealed the beneficial effects of tilorone on HFD and highlight its therapeutic potential in MASLD, particularly given that tilorone is a synthetic small molecule and can be administered orally. Further studies are required to explore its clinical application.\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01685-8","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T02:49:35Z","timestamp":1748314175000},"page":"1097-1114","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tilorone attenuates high-fat diet-induced hepatic steatosis by enhancing BMP9-Smad1\/5\/8 signaling"],"prefix":"10.1007","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3953-7107","authenticated-orcid":false,"given":"Barnabas","family":"Horvath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9834-8619","authenticated-orcid":false,"given":"Judit","family":"Halasz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7252-0250","authenticated-orcid":false,"given":"Norman Noel","family":"Tanner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8299-105X","authenticated-orcid":false,"given":"Zoltan Marton","family":"Kohler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6456-6212","authenticated-orcid":false,"given":"Gyorgy","family":"Trencsenyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-9572","authenticated-orcid":false,"given":"Laszlo","family":"Juhasz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1782-1756","authenticated-orcid":false,"given":"Laszlo","family":"Rovo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7453-3163","authenticated-orcid":false,"given":"Andras","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-8458","authenticated-orcid":false,"given":"Aniko","family":"Keller-Pinter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"issue":"3","key":"1685_CR1","doi-asserted-by":"publisher","first-page":"e159","DOI":"10.1016\/S2468-2667(19)30019-2","volume":"4","author":"AY Chang","year":"2019","unstructured":"Chang AY, et al. 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