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The protective effects of cyclic guanosine monophosphate (cGMP)\u2014protein kinase G (PKG) pathway on heart have been widely reported. Despite phosphodiesterase 9A (PDE9A) inhibitors combating cardiac remodeling, clinically available drugs are lacking. Hederagenin (HED) is a natural bioactive compound that possesses a wide range of pharmacological activities. However, the role of HED in cardiac remodeling and its underlying mechanisms remains elusive. This study aimed to investigate the effects of HED on cardiac remodeling and its molecular targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Procedure<\/jats:title>\n                    <jats:p>Through models of cells, zebrafish and mice, we investigated the effects of HED on cardiac hypertrophic response. In mice subjected to ISO\u2010induced hypertrophy, HED was administered orally at doses of 1.25, 2.5, and 5\u2009mg\/kg once daily for 3\u2009weeks. HuProt v4.0 20K Human Proteome Microarray was used to identify the molecular target of HED, followed by validation using surface plasmon resonance (SPR), molecular docking, and site\u2010directed mutagenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>HED attenuated hypertrophy and fibrotic responses in\u00a0vitro and in\u00a0vivo. Proteome microarrays identified PDE9A as the molecular target of HED. HED directly bound to PDE9A through hydrogen bonds of Asp 293, and inhibited its activity. Functional tests demonstrated that the protective effects of HED were mediated by targeting PDE9A and then activating cGMP\u2010PKG signaling. Overexpression of PDE9A abolished the protective effect of HED on cardiac remodeling and the activation of the cGMP\u2010PKG pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Our study suggested that HED, as a novel PDE9A inhibitor, ameliorated cardiac hypertrophic response by activating the cGMP\u2010PKG signaling pathway, presenting a potential therapeutic strategy for heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ptr.70288","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:35:02Z","timestamp":1772966102000},"page":"2710-2729","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hederagenin Attenuates Cardiac Remodeling by Targeting Phosphodiesterase\n                    <scp>9A<\/scp>"],"prefix":"10.1002","volume":"40","author":[{"given":"Liqian","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine, Nanfang Hospital Southern Medical University  Guangzhou Guangdong China"},{"name":"School of Traditional Chinese Medicine Southern Medical University  Guangzhou Guangdong China"},{"name":"The Affiliated Traditional Chinese Medicine Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghong","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine Southern Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"You","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine Southern Medical University  Guangzhou Guangdong 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