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Complementary experiments were performed in human cardiac-derived cells exposed to simulated ischemia\u2013reoxygenation (sIR) with pharmacological modulation of Epac1, PKA, Akt, and STAT3.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IPC and \u03b2-PC significantly reduced infarct size in WT hearts but failed to confer protection in Epac1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      hearts, demonstrating that Epac1 is essential for IPC- and \u03b2-PC mediated cardioprotection. Consistently, pharmacological inhibition of Epac1 abolished IPC- and \u03b2-PC induced protection in vitro\n                      <jats:italic>.<\/jats:italic>\n                      Direct activation of Epac1 with the selective agonist I942 markedly reduced cell death and increased phosphorylation of Akt, GSK3\u03b2, and STAT3. Inhibition of Akt or STAT3 completely eliminated Epac1-mediated protection, indicating that both RISK- and SAFE-associated signaling are required. In contrast, selective PKA activation failed to induce protection in either WT or Epac1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      hearts, although PKA inhibition partially attenuated IPC- and \u03b2-PC-induced protection, consistent with a permissive rather than primary effector role for PKA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Epac1 mediates IPC and \u03b2-PC induced cardioprotection through Akt\/GSK3\u03b2- and STAT3-dependent signaling, supporting Epac1 as a promising \u03b2-AR-independent therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10557-026-07963-7","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:53:12Z","timestamp":1791521592000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epac1 Functions as a Central Cardioprotective cAMP Effector During Ischemic and \u03b2-adrenergic Preconditioning"],"prefix":"10.1007","author":[{"given":"M. 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