{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T06:14:37Z","timestamp":1780726477261,"version":"3.54.1"},"reference-count":157,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"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>Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disorder worldwide, driven by metabolic dysfunction, excessive lipid accumulation, and progressive hepatocellular injury. A growing body of evidence identifies mitochondrial impairment as a central contributor to MAFLD pathogenesis and disease progression. Reduced oxidative capacity, elevated reactive oxygen species, and accumulation of dysfunctional mitochondria collectively exacerbate steatosis, inflammation, and metabolic inflexibility. In recent years, therapeutic strategies aimed at restoring mitochondrial homeostasis have gained considerable attention, with particular focus on agents capable of inducing mitochondrial biogenesis through pathways involving PGC-1\u03b1, AMPK, SIRT1, and mTOR. This review synthesizes current knowledge on mitochondrial dysfunction in MAFLD and highlights emerging compounds that ameliorate disease phenotypes by enhancing mitochondrial biogenesis. By examining their mechanisms of action and preclinical efficacy, we underscore the therapeutic potential of targeting mitochondrial quality-control pathways, mainly mitochondrial biogenesis, as a promising avenue for mitigating MAFLD progression.<\/jats:p>","DOI":"10.3390\/ijms27062599","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:23:03Z","timestamp":1773307383000},"page":"2599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Jos\u00e9 S.","family":"Morgado","sequence":"first","affiliation":[{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"},{"name":"CNC-UC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CiBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9666-4594","authenticated-orcid":false,"given":"Ivo F.","family":"Machado","sequence":"additional","affiliation":[{"name":"CNC-UC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CiBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Doctoral Program in Experimental Biology and Biomedicine (PDBEB), Institute of Interdisciplinary Research, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela P.","family":"Rolo","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"},{"name":"CNC-UC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CiBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-7697","authenticated-orcid":false,"given":"Carlos M.","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"},{"name":"CNC-UC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CiBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.cmet.2023.02.003","article-title":"The Global Burden of Metabolic Disease: Data from 2000 to 2019","volume":"35","author":"Chew","year":"2023","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2022.0365","article-title":"Global Incidence and Prevalence of Nonalcoholic Fatty Liver Disease","volume":"29","author":"Teng","year":"2023","journal-title":"Clin. 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