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Adv."],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:p>\n                    Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent condition associated with substantial morbidity and mortality, yet effective therapeutic options remain limited. As oxidation of Cys\n                    <jats:sup>42<\/jats:sup>\n                    in cyclic guanosine monophosphate (cGMP)-dependent protein kinase I\u03b1 (PKGI\u03b1) can enhance vessel and diastolic relaxation, processes impaired in HFpEF, we sought to target this mechanism using natural compounds with predicted thiol reactivity. Among these, urolithin A emerged as a compound with a previously unidentified and counterintuitive mode of action, directly modifying Cys\n                    <jats:sup>42<\/jats:sup>\n                    in PKGI\u03b1. In a multihit HFpEF model that closely mimics the human condition, urolithin A improved diastolic function and attenuated cardiac remodeling through cysteine 42\u2013dependent activation of PKGI\u03b1. These findings were further validated in human engineered heart tissue, where urolithin A enhanced both relaxation and contraction kinetics. These findings collectively highlight Cys\n                    <jats:sup>42<\/jats:sup>\n                    in PKGI\u03b1 as a promising therapeutic target for HFpEF and identify urolithin A as a previously unidentified activator of this protective mechanism.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec8088","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:59:26Z","timestamp":1787162366000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Targeting PKGI\u03b1 Cys\n                    <sup>42<\/sup>\n                    attenuates cardiac dysfunction in heart failure with preserved ejection fraction"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6579-3904","authenticated-orcid":true,"given":"Jie","family":"Su","sequence":"first","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine &amp; Sciences, King\u2019s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas\u2019 Hospital, London SE1 7EH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6818-2352","authenticated-orcid":true,"given":"Yue","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine &amp; 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Sciences, King\u2019s College London, The British Heart Foundation Centre of Excellence, Randall Centre for Cell and Molecular Biophysics, New Hunt\u2019s House, London SE1 1UL, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7547-1514","authenticated-orcid":true,"given":"Janice","family":"Raabe","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1612-1715","authenticated-orcid":true,"given":"Friederike","family":"Cuello","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6547-0631","authenticated-orcid":true,"given":"Ajay","family":"Shah","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Medicine &amp; 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