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The underlying molecular mechanisms are not fully understood. Transcription factor FOXM1 plays an essential role in cardiovascular development. The present study explores its role in mitochondrial bioenergetics in postmitotic cardiomyocytes (CMs). FOXM1 is significantly upregulated in ischemic heart tissues from humans, mice, and pigs. CM\u2010specific <jats:italic>Foxm1<\/jats:italic>\u2010knockout mice exhibit dilated cardiomyopathy features associated with mitochondrial dysfunction. Transcriptomic and proteomic profiling of <jats:italic>Foxm1<\/jats:italic>\u2010knockout mice reveal robust, specific downregulation of gene programs important for mitochondrial energetics and homeostasis. Analysis of proteome and ubiquitinome data reveal that FOXM1 deficiency in CMs promotes LKB1 ubiquitination and impairs the AMPK signaling and energy metabolism pathways. Bioinformatics analysis identifies that E3 ligase MKRN1 promotes the K48\u2010linked ubiquitination of LKB1 on Lys146, which in turn, inhibits the AMPK signaling pathway and impairs energy homeostasis in mice with HF. CM\u2010specific <jats:italic>Mkrn1<\/jats:italic> knockout ameliorates cardiac dysfunction by rejuvenating the impaired mitochondrial bioenergetics induced by FOXM1 deficiency. FOXM1 overexpression preserves mitochondrial bioenergetics and protects against myocardial I\/R injury in both rodent and porcine models. In conclusion, FOXM1 is actively involved in mitochondrial bioenergetics during HF. FOXM1 may be a potential promising therapeutic target for myocardial I\/R injury and HF.<\/jats:p>","DOI":"10.1002\/advs.202508673","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T05:27:07Z","timestamp":1750656427000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["FOXM1 Protects Against Myocardial Ischemia\u2010Reperfusion Injury in Rodent and Porcine Models by Suppressing MKRN1\u2010Dependent LKB1 Ubiquitination"],"prefix":"10.1002","volume":"12","author":[{"given":"Shuai","family":"Song","sequence":"first","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai 200032 China"},{"name":"Key Laboratory of Viral Heart Diseases National Health Commission  Shanghai 200032 China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai 200032 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