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Reperfusion, although essential for myocardial restoration, can paradoxically exacerbate injury through oxidative stress, calcium overload, mitochondrial permeability transition pore opening and inflammatory infiltration. The vulnerability to MIRI is substantially amplified in subjects with diabetes mellitus, where chronic hyperglycemia, insulin resistance, and the resulting oxidative stress and low\u2010grade inflammation impair endogenous cardioprotective mechanisms and worsen postinfarction outcomes. Ischemic conditioning strategies, including preconditioning and postconditioning, serve as powerful innate methods to mitigate MIRI by exposing the myocardium to brief, sublethal ischemic episodes that activate crucial prosurvival signalling pathways. Among these pathways, the survivor activating factor enhancement pathway, which is mediated predominantly by signal transducer and activator of transcription 3 (STAT3), and the reperfusion injury salvage kinase pathway, which involves AKT and ERK, are particularly important. However, in many models of diabetes, diabetes\u2010induced STAT3 dysfunction may disrupt these protective pathways, often making conditioning stimuli less effective. The precise mechanisms underlying this impairment remain incompletely understood. Additionally, paradoxical changes in STAT3 expression have been reported, and key posttranslational modifications of STAT3 have not yet been investigated in the context of diabetic MIRI. This review provides a critical appraisal of the role, regulatory mechanisms and therapeutic potential of STAT3 in ischemic conditioning in patients with diabetes and discusses strategies aimed at restoring cardioprotection in this high\u2010risk population.<\/jats:p>","DOI":"10.1111\/jcmm.71418","type":"journal-article","created":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:52:43Z","timestamp":1792813963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting STAT3 to Modulate the Effectiveness of Cardioprotective Conditioning Strategies Against Myocardial Ischemia\u2013Reperfusion Injury in Subjects With Diabetic Cardiomyopathy"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1441-5971","authenticated-orcid":false,"given":"Chunyan","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Trauma and Metabolism Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"},{"name":"Department of Anesthesiology Shenzhen Maternity and Child Healthcare Hospital  Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0933-6163","authenticated-orcid":false,"given":"Wangli","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Saedi","sequence":"additional","affiliation":[{"name":"Institute of Trauma and Metabolism Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"},{"name":"Cell Research and Transformation Center Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengzhen","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Shenzhen Maternity and Child Healthcare Hospital  Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinjun","family":"Chu","sequence":"additional","affiliation":[{"name":"Cell Research and Transformation Center Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6844-5928","authenticated-orcid":false,"given":"Zhengyuan","family":"Xia","sequence":"additional","affiliation":[{"name":"Institute of Trauma and Metabolism Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"},{"name":"Department of Anesthesiology and Perioperative Medicine Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"},{"name":"Cell Research and Transformation Center Zhengzhou Central Hospital Affiliated With Zhengzhou University  Zhengzhou China"},{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine The University of Hong Kong  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"e_1_2_17_2_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-026-71232-2","article-title":"Cardiomyocyte\u2010Derived GPX4 Stabilizes BNIP3 to Facilitate Mitophagy and Mitigate Myocardial Ischemia\/Reperfusion Injury","volume":"17","author":"Zhong L.","year":"2026","journal-title":"Nature Communications"},{"key":"e_1_2_17_3_1","first-page":"10","article-title":"Myocardial Ischemia\/Reperfusion: Translational Pathophysiology of Ischemic Heart Disease","volume":"5","author":"Heusch G.","year":"2024","journal-title":"Medicus"},{"key":"e_1_2_17_4_1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.3892\/etm.2022.11357","article-title":"Myocardial Ischemia\/Reperfusion Injury: Mechanisms of Injury and Implications for Management (Review)","volume":"23","author":"He J.","year":"2022","journal-title":"Experimental and Therapeutic Medicine"},{"key":"e_1_2_17_5_1","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41569-020-0403-y","article-title":"Myocardial Ischaemia\u2010Reperfusion Injury and Cardioprotection in Perspective","volume":"17","author":"Heusch G.","year":"2020","journal-title":"Nature Reviews. 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