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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Metabolic-associated steatotic liver disease (MASLD) affects an estimated 25\u201330% of the global adult population and represents a leading cause of liver-related morbidity. However, approved pharmacological therapies remain strictly limited. AMP-activated protein kinase (AMPK), a highly conserved heterotrimeric serine\/threonine kinase and major regulator of cellular energy homeostasis, is chronically suppressed in the steatotic liver through hyperinsulinemia, ceramide signaling, oxidative stress, and epigenetic silencing of its upstream activator LKB1. This suppression removes a critical brake on de novo lipogenesis while simultaneously impairing fatty acid \u03b2-oxidation, mitochondrial quality control, anti-inflammatory signaling, and hepatic stellate cell quiescence. Thus, AMPK restoration may serve as an effective strategy capable of addressing multiple pathological drivers of MASLD. This review examines the molecular architecture of the AMPK heterotrimer, the downstream signaling networks governing hepatic lipid metabolism, glucose homeostasis, and fibrogenesis, and a spectrum of AMPK-activating pharmacology relevant to MASLD. Furthermore, it would introduce indirect activators including metformin, berberine, resveratrol, and related phytochemicals, as well as direct allosteric activators targeting the ADaM site, such as A-769662, PF-06409577, MK-8722, Compound 991, and the clinical-stage compound O304. Translational challenges confronting this therapeutic class are critically evaluated.<\/jats:p>","DOI":"10.3390\/ijms27188358","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:23:56Z","timestamp":1790864636000},"page":"8358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AMPK-Directed Therapeutics for MASLD: Mechanistic Rationale, Activator Classes, and Clinical Translation"],"prefix":"10.3390","volume":"27","author":[{"given":"Reeju","family":"Amatya","sequence":"first","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Gyeongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7586-4815","authenticated-orcid":false,"given":"Ji Yeon","family":"Hyun","sequence":"additional","affiliation":[{"name":"Phytoeco, Inc., Bldg. B, Room 404, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea"},{"name":"Wasong Agricultural Co., Ltd., Bldg. B, Room 403, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Hak","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0767-4927","authenticated-orcid":false,"given":"Kyoung Ah","family":"Min","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, 197 Injero, Gimhae 50834, Gyeongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8035-923X","authenticated-orcid":false,"given":"Meong Cheol","family":"Shin","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju 52828, Gyeongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.tem.2024.02.007","article-title":"Current status and future trends of the global burden of MASLD","volume":"35","author":"Miao","year":"2024","journal-title":"Trends Endocrinol. 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