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bioRxiv · 10.1101/2025.02.22.639635

Targeting the ferroptosis pathway: A novel compound, AZD1390, protects the brain after ischemic stroke

Lee, H. K.·LIN, C.-C.·Dunn, D. E.·Chen, Y.·Chen, S.-Y.·Marchuk, D. A.·Floyd, S. R.·Chi, J.-T. A.
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Abstract

BackgroundFerroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. This process has been implicated in various diseases, including ischemic stroke. Ischemic stroke leads to oxidative stress, iron overload, and reactive oxygen species (ROS) accumulation, which collectively may trigger ferroptotic neuronal cell death. However, the regulatory mechanisms of ferroptosis in stroke remain poorly understood. Previous studies have identified ataxia telangiectasia mutated (ATM), a DNA damage kinase, as a critical regulator of ferroptosis. However, the therapeutic potential of this discovery remains unknown. MethodsWe investigated the effect of ATM inhibitors, including the brain-penetrant AZD1390, on ferroptosis using in vitro, ex vivo, and in vivo models of ischemic stroke. Our analysis included assessments of cell viability, lipid peroxidation, ferroptosis marker expression, and infarct volume. ResultATM inhibitors significantly alleviated ferroptosis-induced cell death in cultured cells and ex vivo murine brain slice cultures. In the oxygen-glucose deprivation (OGD) stroke model, treatment with AZD1390 reduced the expression of ferroptosis markers (xCT and PTGS2) and diminished neuronal cell death in rat and mouse brain slices. Furthermore, in a mouse model of ischemic stroke, AZD1390 decreased infarct volume confirming its therapeutic efficacy in vivo. ConclusionsThis study identifies ferroptosis as a critical mechanism in ischemic stroke-induced neuronal cell death and highlights ATM inhibition, particularly with AZD1390, as a promising therapeutic candidate for mitigating stroke-associated damage. Targeting ferroptosis may provide a translationally relevant strategy to mitigate neuronal injury and improve clinical outcomes for stroke patients.

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Lee, H. K., LIN, C.-C., Dunn, D. E., Chen, Y., Chen, S.-Y., Marchuk, D. A., Floyd, S. R., Chi, J.-T. A.. 2025-02-25. Targeting the ferroptosis pathway: A novel compound, AZD1390, protects the brain after ischemic stroke. https://doi.org/10.1101/2025.02.22.639635

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