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BackgroundThe causal relationship between the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the preservation of SERCA2a function in mitigating myocardial ischemia–reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. This study aims to unravel how NRF2 directly or indirectly influences SERCA2a function and its regulators, phospholamban (PLN) and Dwarf Open Reading Frame (DWORF), by testing the pharmacological repositioning of AEOL-10150 (AEOL) in the context of mI/R injury.MethodsC57BL6/J, Nrf2 knockout (Nrf2?/?), and wild-type (Nrf2+/+) mice, as well as human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were subjected to I/R injury. Gain/loss of function techniques, RT-qPCR, western blotting, LC/MS/MS, and fluorescence spectroscopy were utilized. Cardiac dimensions and function were assessed by echocardiography.ResultsIn the early stages of mI/R injury, AEOL administration reduced mitochondrial ROS production, decreased myocardial infarct size, and improved cardiac function. These effects were due to NRF2 activation, leading to the overexpression of the micro-peptide DWORF, consequently enhancing SERCA2a activity. The cardioprotective effect induced by AEOL was diminished in Nrf2?/? mice and in Nrf2/Dworf knockdown models in hiPSCMs subjected to simulated I/R injury. Our data show that AEOL-induced NRF2-mediated upregulation of DWORF disrupts the phospholamban-SERCA2a interaction, leading to enhanced SERCA2a activation and improved cardiac function.ConclusionsTaken together, our study reveals that AEOL-induced NRF2-mediated overexpression of DWORF enhances myocardial function through the activation of the SERCA2a offering promising therapeutic avenues for mI/R injury.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10020-025-01242-1. Highlights• Novel AEOL-10150 therapeutic potential. AEOL-10150 demonstrates promise in activating NRF2 and mitigating myocardial ischemia-reperfusion injury.• DWORF overexpression breakthrough. Overexpression of DWORF significantly contributes to preserving cardiac function and reducing myocardial injury through the NRF2-DWORF pathway.• Enhanced cardiac protection mechanisms. The study highlights the dual role of AEOL-10150 and DWORF in enhancing cardiac protection and preventing heart failure.• Future research directions. Additional studies are required to validate the long-term efficacy of AEOL-10150 and the regulatory effects of NRF2-DWORF axis in clinical applications.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10020-025-01242-1.

ABSTRACTPropionic acidemia (PA) is a metabolic disorder caused by a deficiency of the mitochondrial enzyme propionyl?CoA carboxylase (PCC) due to mutations in the PCCA or PCCB genes, which encode the two PCC subunits. PA may lead to several types of cardiomyopathy and has been linked to cardiac electrical abnormalities such as QT interval prolongation, life?threatening arrhythmias, and sudden cardiac death. To gain insights into the mechanisms underlying PA?induced proarrhythmia, we recorded action potentials (APs) and ion currents using whole?cell patch?clamp in ventricular?like induced pluripotent stem cells?derived cardiomyocytes (hiPSC?CMs) from a PA patient carrying two pathogenic mutations in the PCCA gene (p.Cys616_Val633del and p.Gly477Glufs*9) (PCCA cells) and from a healthy subject (healthy cells). In cells driven at 1?Hz, PCC deficiency increased the latency and prolonged the AP duration (APD) measured at 20% of repolarization, without modifying resting membrane potential or AP amplitude. Moreover, delayed afterdepolarizations appeared at the end of the repolarization phase in unstimulated and paced PCCA cells. PCC deficiency significantly reduced peak sodium current (I Na) but increased the late I Na (I NaL) component. In addition, L?type Ca2+ current (I CaL) density was reduced, while the inward and outward density of the Na+/Ca2+ exchanger current (I NCX) was increased in PCCA cells compared to healthy ones. In conclusion, our results demonstrate that at the cellular level, PCC deficiency can modify the ion currents controlling cardiac excitability, APD, and intracellular Ca2+ handling, increasing the risk of arrhythmias independently of the progressive late?onset cardiomyopathy induced by PA disease.