ATM inhibition attenuates ferroptosis-associated injury and reduces infarct volume in experimental stroke
- 1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27705, USA.
- 2Duke Center for Genomic and Computational Biology, Duke University, Durham, NC 27705, USA.
- 3Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27705, USA.
Abstract
Aims:: Ferroptosis, an iron-dependent form of regulated cell death, contributes to neuronal injury after ischemic stroke. Because our previous cancer-cell screens identified ataxia-telangiectasia mutated (ATM) kinase, as a ferroptosis regulator, we investigated whether ATM inhibition protects neural tissue after ischemic stroke and examined determinants of therapeutic response.
Methods:: ATM inhibitors, including the brain-penetrant clinical compound AZD1390, were evaluated in cultured cancer and neuronal cells, oxygen-glucose-deprived rat and mouse brain slices, and permanent middle cerebral artery occlusion models using multiple inbred and Rabep2-genotype mouse strains. Cell viability, cytotoxicity, lipid peroxidation, ferroptosis-associated markers, infarct volume, and collateral vessel density were assessed. Topical AZD1390 was also tested in mice with impaired collateral networks.
Results:: ATM inhibition reduced ferroptosis-associated lipid oxidative injury and protected neurons in multiple preclinical stroke models. AZD1390 decreased lipid peroxidation and neuronal death, and reduced infarct volume in B6/J and B6/NJ mice, but not in BALB mice. Treatment efficacy varied among strains and was correlated with collateral vascular density. Systemic AZD1390 was likewise ineffective in Rabep2-knockout mice with deficient collateral networks. Early topical administration also reduced infarct volume in mice with limited collateral networks; however, differences in treatment timing and route preclude direct attribution to improved local drug delivery.
Conclusion:: ATM inhibition may attenuate ferroptosis-associated neuronal injury after ischemic stroke, while collateral vascular anatomy may influence therapeutic response. These findings support further mechanistic and translational evaluation of ferroptosis-targeting strategies in stroke.
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BibTeX
@article{lee2026inhibition,
title = {{ATM inhibition attenuates ferroptosis-associated injury and reduces infarct volume in experimental stroke}},
author = {Han Kyu Lee and Chao-Chieh Lin and Denise E. Dunn and Yubin Chen and Ssu-Yu Chen and Douglas A. Marchuk and Scott R. Floyd and Jen-Tsan Chi},
journal = {Ferroptosis and oxidative stress},
year = {2026},
month = sep,
doi = {10.70401/fos.2026.0046},
url = {https://doi.org/10.70401/fos.2026.0046},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ATM inhibition attenuates ferroptosis-associated injury and reduces infarct volume in experimental stroke
AU - Han Kyu Lee
AU - Chao-Chieh Lin
AU - Denise E. Dunn
AU - Yubin Chen
AU - Ssu-Yu Chen
AU - Douglas A. Marchuk
AU - Scott R. Floyd
AU - Jen-Tsan Chi
PY - 2026
DA - 2026/09/22
JO - Ferroptosis and oxidative stress
DO - 10.70401/fos.2026.0046
UR - https://doi.org/10.70401/fos.2026.0046
AB - Aims:: Ferroptosis, an iron-dependent form of regulated cell death, contributes to neuronal injury after ischemic stroke. Because our previous cancer-cell screens identified ataxia-telangiectasia mutated (ATM) kinase, as a ferroptosis regulator, we investigated whether ATM inhibition protects neural tissue after ischemic stroke and examined determinants of therapeutic response. Methods:: ATM inhibitors, including the brain-penetrant clinical compound AZD1390, were evaluated in cultured cancer and neuronal cells, oxygen-glucose-deprived rat and mouse brain slices, and permanent middle cerebral artery occlusion models using multiple inbred and Rabep2-genotype mouse strains. Cell viability, cytotoxicity, lipid peroxidation, ferroptosis-associated markers, infarct volume, and collateral vessel density were assessed. Topical AZD1390 was also tested in mice with impaired collateral networks. Results:: ATM inhibition reduced ferroptosis-associated lipid oxidative injury and protected neurons in multiple preclinical stroke models. AZD1390 decreased lipid peroxidation and neuronal death, and reduced infarct volume in B6/J and B6/NJ mice, but not in BALB mice. Treatment efficacy varied among strains and was correlated with collateral vascular density. Systemic AZD1390 was likewise ineffective in Rabep2-knockout mice with deficient collateral networks. Early topical administration also reduced infarct volume in mice with limited collateral networks; however, differences in treatment timing and route preclude direct attribution to improved local drug delivery. Conclusion:: ATM inhibition may attenuate ferroptosis-associated neuronal injury after ischemic stroke, while collateral vascular anatomy may influence therapeutic response. These findings support further mechanistic and translational evaluation of ferroptosis-targeting strategies in stroke.
ER -