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Prior to clinical studies, it is essential to identify potential translational roadblocks. One such barrier is the metabolic signature of the heart. Here, we explored whether and how the metabolic signature of the heart drive cardiac IRI and modulate malonate protection. Langendorff-perfused mouse hearts were subjected to 30 min ischemia (I) followed by 90 min reperfusion (R), with or without 5mM disodium malonate administered during the first 5 min reperfusion. Cardiac IRI and malonate protection were examined under four metabolic conditions increasing in metabolic complexity: glucose-only (G), glucose\u2009+\u2009glutamine (GG), GG\u2009+\u2009fatty acid (F), F\u2009+\u2009insulin (Ins). Metabolomic profiling and survival kinases were evaluated at end-ischemia and at 7 min of reperfusion\u2009\u00b1\u2009malonate. Additional experiments examined the effects of glucose, lactate, and low pH on malonate efficacy. IRI (% infarct size) increased with metabolic complexity: 32\u2009\u00b1\u200911% (G), 38\u2009\u00b1\u200911%(GG), 52\u2009\u00b1\u200914% (F), and 68\u2009\u00b1\u200910% (Ins). Malonate reduced IS% in the G (-27%), GG (-45%) and F (-23%) groups, but not in the Ins group (-12%, not significant). Malonate increased the glycolytic activator and protectant fructose-1\/2,6-bisphosphate, mitochondrially bound hexokinase 1 and ATP across all metabolic conditions, confirming measurements showing cellular malonate uptake in all metabolic conditions. Loss of protection correlated with elevated pre-ischemic glycogen levels, end-ischemic lactate levels and delayed ischemic contracture, both indicative of prolonged glycolysis during ischemia due to glycogen loading, and increased glycolytic intermediates during early reperfusion hallmarks of cardiac glucose loading. Indeed, protection was restored in the insulin group when glucose was withheld prior to ischemia. With glucose present before ischemia, elevated lactate and lower pH were observed at onset reperfusion. Further experiments revealed that lower pH\u2014not elevated lactate\u2014at reperfusion was responsible for the loss of malonate protection. Disodium malonate (120 mg\/kg) was also unable to reduce infarct size in an in vivo rat model of cardiac IRI employing similar insulin levels as used in the Langendorff-perfused mouse heart model. While malonate offers robust protection against cardiac IRI across various metabolic environments, its efficacy is compromised under conditions of high ischemic glycogen breakdown, which leads to severe acidosis at the onset of reperfusion that was associated with the loss of malonate protection.<\/jats:p>","DOI":"10.1007\/s00395-026-01206-4","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T11:25:47Z","timestamp":1786965947000},"page":"863-882","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic dependency of malonate protection against cardiac ischemia\u2013reperfusion injury"],"prefix":"10.1007","volume":"121","author":[{"given":"Qian","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne","family":"Nederlof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiota-Efstathia","family":"Nikolaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Chania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Bakker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita Kim","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus W.","family":"Hollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina C.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bauke","family":"Schomakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"van Weeghel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8361-2448","authenticated-orcid":false,"given":"Coert J.","family":"Zuurbier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"1206_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-024-01063-z","author":"J Abe","year":"2024","unstructured":"Abe J, Vujic A, Prag HA, Murphy MP, Krieg T (2024) Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia\/reperfusion injury. 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