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Disrupted endoplasmic reticulum (ER) homeostasis is recognized as a central mechanism in its pathogenesis. Although the homologous kinases Pak1 and Pak2 regulate the ER stress response, the role of Pak1 in HFpEF remains unclear. This study demonstrates that Pak1 is a critical regulator of cardiac adaptation to metabolic stress. Using a murine HFpEF model combining high\u2011fat diet and nitric oxide synthase inhibition, Pak1 knockdown accelerates diastolic dysfunction and maladaptive remodeling, accompanied by disrupted ER ultrastructure and impaired PERK\u2011ATF4 signaling, whereas Pak1 overexpression preserves cardiac function and ER homeostasis. Mechanistically, Pak1 activates the ERK1\/2\u2010MNK1\u2010eIF4E signaling axis and promotes adaptive integrated stress response (ISR) signaling through the PERK\u2010ATF4 pathway. Pharmacological inhibition of MNK1 attenuated Pak1\u2010mediated PERK activation and ATF4 induction, identifying a mechanistic link between Pak1 signaling and adaptive stress responses. Furthermore, we developed a novel small\u2010molecule Pak1 activator, JB2019, which reversed metabolic stress\u2010induced cardiac dysfunction in both HFpEF mice and cardiac organoids. Collectively, these findings identify Pak1 as a novel regulator of adaptive ISR signaling and establish Pak1 activation as a promising therapeutic strategy for HFpEF.<\/jats:p>","DOI":"10.1002\/advs.76964","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:52:09Z","timestamp":1785754329000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Pak1 Activator Ameliorates ER Stress for HFpEF Therapy"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8889-8941","authenticated-orcid":false,"given":"Honglin","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6099-0494","authenticated-orcid":false,"given":"Tayyiba","family":"Azam","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9809-4636","authenticated-orcid":false,"given":"Susanne S.","family":"Hille","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III University of Kiel  Kiel Germany"},{"name":"German Center for Cardiovascular Research (DZHK) Partner Site Hamburg\/Kiel\/Luebeck  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4183-1818","authenticated-orcid":false,"given":"Min","family":"Zi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqing","family":"Lang","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Function, School of Biological Sciences The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1572-2618","authenticated-orcid":false,"given":"Yujia","family":"Cao","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard D.","family":"Keavney","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Science, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8435-808X","authenticated-orcid":false,"given":"Tamer M. 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