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Consequently, it has emerged as a target for pharmacological activators in the treatment of endothelial dysfunction. However, the efficiency of these agonists may differ depending on the expression of different AMPK subunit isoforms in different cells and tissues, as these isoforms may form AMPK complexes with distinct activation profiles. The present study compares the effects of three direct AMPK activators in endothelial cells: MK-8722, a pan-AMPK activator; SC4, an intermediate activator with preference for AMPK\u03b12; and A-769662, a \u03b21-specific compound. We demonstrate that MK-8722 (0.1\u00a0to 10\u00a0\u03bcM) induces a robust and sustained, short- and long-term activation of AMPK, as evidenced by the phosphorylation of acetyl-CoA carboxylase and the inhibition of the mechanistic target of rapamycin complex 1 pathway. On an equimolar basis, MK-8722 was significantly more potent than SC4 and A-769662. This was associated with a significant antiviral effect of MK-8722 against herpes simplex virus type 1, whereas SC4 and A-769662 had no effect. At 10\u00a0\u03bcM, MK-8722 led to energy depletion and increased formation of mitochondrial and cytosolic reactive oxygen species due to inhibition of mitochondrial complex I. Under these conditions, liver kinase B1-mediated AMPK activation was observed but was not functionally relevant. We propose that the strong activation of AMPK by MK-8722 is related to the presence of different AMPK heterotrimers in endothelial cells. Therefore, targeting endothelial dysfunction pharmacologically may require pan-AMPK activators.<\/jats:p>","DOI":"10.1042\/bsr20250408","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:37:39Z","timestamp":1788874659000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The pan-AMPK activator MK-8722 outperforms the AMPK activators SC4 and A-769662 in human endothelial cells"],"prefix":"10.1042","volume":"46","author":[{"given":"Heena","family":"Doshi","sequence":"first","affiliation":[{"name":"1Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Spengler","sequence":"additional","affiliation":[{"name":"1Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanstantsin","family":"Siniuk","sequence":"additional","affiliation":[{"name":"2Leibniz Institute on Aging- Fritz Lipmann Institute (FLI), 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Groth","sequence":"additional","affiliation":[{"name":"2Leibniz Institute on Aging- Fritz Lipmann Institute (FLI), 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Heyne","sequence":"additional","affiliation":[{"name":"3Department of Cardiothoracic Surgery, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schwarzer","sequence":"additional","affiliation":[{"name":"3Department of Cardiothoracic Surgery, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amod","family":"Godbole","sequence":"additional","affiliation":[{"name":"1Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u00a0Sing","family":"Gee","sequence":"additional","affiliation":[{"name":"4Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Baell","sequence":"additional","affiliation":[{"name":"4Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia"},{"name":"5School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan\u00a0S.","family":"Oakhill","sequence":"additional","affiliation":[{"name":"6Metabolic Signaling Laboratory, St. Vincent\u2019s Institute of Medical Research, Fitzroy 3065, Australia"},{"name":"7Faculty of Health Sciences, Australian Catholic University, Melbourne 3065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Henke","sequence":"additional","affiliation":[{"name":"8Section of Experimental Virology, Institute of Medical Microbiology, Jena University Hospital, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1703-1925","authenticated-orcid":false,"given":"Regine","family":"Heller","sequence":"additional","affiliation":[{"name":"1Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"2026092204020397700_B1","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/s41569-025-01162-x","article-title":"Endothelial cell metabolism in cardiovascular physiology and disease","volume":"22","author":"Pasut","year":"2025","journal-title":"Nat. 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