{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:28:17Z","timestamp":1791044897541,"version":"4.1.0"},"reference-count":151,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The introduction of the term \u201cMetabolic Steatotic Liver Disease\u201d (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver\u2019s increased production of proteins known as \u201chepatokines\u201d has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.<\/jats:p>","DOI":"10.3390\/ijms251910795","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T12:02:10Z","timestamp":1728388930000},"page":"10795","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target"],"prefix":"10.3390","volume":"25","author":[{"given":"Ilaria","family":"Milani","sequence":"first","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1562-4495","authenticated-orcid":false,"given":"Michela","family":"Codini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Guarisco","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Chinucci","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Gaita","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frida","family":"Leonetti","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1674-6686","authenticated-orcid":false,"given":"Danila","family":"Capoccia","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100485","DOI":"10.1016\/j.jlr.2023.100485","article-title":"From NAFLD to MASLD: Updated naming and diagnosis criteria for fatty liver disease","volume":"65","author":"Rinella","year":"2024","journal-title":"J. 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