['Forkhead box protein O1 (FoxO1) plays a key role in energy homeostasis, stress response and autophagy and is dysregulated in diabetes and ischemia. We investigated cardiac FoxO1 expression and posttranstranslational modifications after myocardial infarction (MI) and further tested if active posttranstranslational modulation of FoxO1 can alter cardiac remodeling in postischemic heart failure.', 'Non-diabetic and diabetic C57BL/6 mice were subjected to MI by ligation of left anterior descending artery. In selected experiments we combined this model with intramyocardial injection of adenovirus expressing different isoforms of FoxO1. We used Millar catheter, histology, Western blot and metabolomics for further analyses.', 'We show that after MI total cardiac FoxO1 is downregulated and partly recovers after 7 days. This downregulation is accompanied by fundamental posttranslational modifications of FoxO1, particularly acetylation. Adenovirus experiments revealed smaller infarction size and improved heart function in mice expressing a constitutively deacetylated variant of FoxO1 compared to a wild type variant of FoxO1 in both non-diabetic (MI size:\xa0-13.4\xa0±\xa03.5%; LVDP:\xa0+29.1\xa0±\xa09.4\xa0\xa0mmHg; p\xa0<\xa00.05) and diabetic mice (MI size:\xa0-17.6\xa0±\xa03.7%; LVDP:\xa0+10.9\xa0±\xa03.6\xa0\xa0mmHg; p\xa0<\xa00.05). Metabolomics analyses showed alterations in metabolites connected to muscle breakdown, collagen/elastin and energy metabolism between the two groups.'] Does posttranslational modulation of FoxO1 contribute to cardiac remodeling in post-ischemic heart failure?