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Cardioprotection aims to mitigate ischemia\/reperfusion injury (IRI) by modulating molecular pathways, such as the Reperfusion Injury Salvage Kinase (RISK) and Survivor Activating Factor Enhancement (SAFE) pathways, as well as autophagy, inflammation, and regulated cell death, to preserve myocardial function. However, a major limitation lies in the robustness of preclinical evidence. Many experimental studies rely on simplified models that fail to reproduce the complexity of human cardiac pathophysiology, resulting in inconsistent and poorly reproducible cardioprotective effects. It is likely that RISK-SAFE pathways represent an oversimplified framework. Moreover, most experimental approaches are cardiomyocyte-centered, overlooking the critical role of the vessels in IRI. Clinical translation is further compromised by patient-related factors, including comorbidities (e.g., diabetes, hypertension), concomitant medications, and heterogeneity in reperfusion protocols, all of which attenuate cardioprotective efficacy. Additional variables, such as timing of intervention and species differences, further contribute to translational failure. Emerging approaches include pharmacological therapies (e.g., SGLT2 inhibitors, PARP inhibitors, necroptosis and ferroptosis blockers, NLRP3-targeting compounds), cell- and organelle-based strategies (e.g., mitochondrial transplantation, extracellular vesicles, non-coding RNAs), and mechanical\/device-based interventions (e.g., left ventricular unloading, ischemic conditioning, controlled reperfusion, selective intracoronary hypothermia). Future research should emphasize multi-target interventions, optimized timing and delivery, and advanced tools, such as nanocarriers, gene therapy, computational modeling, and adaptive clinical trials. Strengthening the robustness of preclinical models, including human ex vivo cardiac systems, remains essential to bridge the translational gap and improve the clinical success of cardioprotective therapies.<\/jats:p>","DOI":"10.1007\/s00395-026-01167-8","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:51:27Z","timestamp":1773424287000},"page":"321-350","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Insights in ischemia\/reperfusion injury and cardioprotection: neglected and emerging pathways and therapeutic targets for a personalized therapy"],"prefix":"10.1007","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4386-1383","authenticated-orcid":false,"given":"Pasquale","family":"Pagliaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9696-0449","authenticated-orcid":false,"given":"C.","family":"Penna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-0784","authenticated-orcid":false,"given":"S.","family":"Femmin\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1802-0491","authenticated-orcid":false,"given":"F. 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