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SATB1/SLC7A11/HO-1 Axis Ameliorates Ferroptosis in Neuron Cells After Ischemic Stroke by Danhong Injection

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Abstract

Neuronal damage after ischemic stroke (IS) is frequently due to ferroptosis, contributing significantly to ischemic injury. However, the mechanism against ferroptosis in IS remained unclear. The aim of this study was to investigate the potential mechanism of Danhong injection (DHI) and the critical transcription factor SATB1 in preventing neuronal ferroptosis after ischemic stroke in vivo and in vitro. The results showed that DHI treatment significantly reduced the infarct area and associated damage in the brains of the pMCAO mice, and enhanced the viability of OGD-injured neurons. And several characteristic indicators of ferroptosis, such as mitochondrial necrosis and iron accumulation, were regulated by DHI after IS. Importantly, we found that the expression and activity of SATB1 were decreased in the pMCAO mice, especially in neuron cells. Meanwhile, the SATB1/SLC7A11/HO-1 signaling pathway was activated after DHI treatment in ischemic stroke and was found to improve neuronal ferroptosis. Inhibition of SATB1 significantly reduced SLC7A11-HO-1 and significantly attenuated the anti-ferroptosis effects of DHI in the OGD model. These findings indicate that neuronal ferroptosis after IS can be alleviated by DHI through SATB1/SLC7A11/HO-1 pathway, and SATB1 may be an attractive therapeutic target for treating ischemic stroke.

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Acknowledgements

We would like to thank Dr. Hongjun Yang at China Academy of Chinese Medical Sciences for stimulating discussion, Dr. Quan Yang for providing experimental apparatus, and Buchang Pharma for providing the DHI injection. Besides, we also thank Yutong Zhang, Meixia Xie, and Bang Liu for the assistance with the experiments and checking this manuscript.

Funding

This study was supported by funds from Projects of the National Natural Science Foundation of China (Grant No. 82004086) and Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (Grant No. 20202103).

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Authors and Affiliations

  1. Guangdong Pharmaceutical University, No. 280, Waihuan East Road, Higher Education Mega Center, Panyu District, Guangzhou, 510006, China

    Sikai Zhan, Jiayin Liang, Huiting Lin, Jiale Cai, Xinxin Yang, Shumei Wang & Minghua Xian

  2. Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Sikai Zhan, Jiayin Liang, Huiting Lin, Jiale Cai, Xinxin Yang, Shumei Wang & Minghua Xian

  3. Engineering & Technology Research Center for Chinese Materia Medica Quality of the Universities of Guangdong Province, School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Sikai Zhan, Jiayin Liang, Huiting Lin, Jiale Cai, Xinxin Yang, Shumei Wang & Minghua Xian

  4. China Academy of Chinese Medical Sciences, Dongzhimen 16 Nanxiao Road, Dongcheng District, Beijing, 100700, China

    Hongwei Wu & Junying Wei

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  1. Sikai Zhan
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Contributions

Sikai Zhan conducted all the experiments and drafted the manuscript. Jiayin Liang, Huiting Lin, and Jiale Cai conducted the experiments and analyzed the data. Xinxin Yang participated in W. B. experiments and analyzed the data. Shumei Wang, Hongwei Wu, and Junying Wei conceived and designed the experiments. Minghua Xian conceived and designed the experiment, and improved the language of the manuscript. All the authors have reviewed and agreed the submission of the manuscript.

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Correspondence to Junying Wei, Shumei Wang or Minghua Xian.

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The animal study was reviewed and approved by the Animal Ethics Committee of Guangdong Pharmaceutical University.

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Highlights

• A new therapeutic function and mechanisms of DHI against neuronal ferroptosis in ischemic stroke were proposed.

• SATB1, as a critical transcription factor, could be a new therapeutic target for treating ischemic stroke.

• SATB1/SLC7A11/HO-1 was proposed as a novel signaling pathway against ferroptosis.

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Zhan, S., Liang, J., Lin, H. et al. SATB1/SLC7A11/HO-1 Axis Ameliorates Ferroptosis in Neuron Cells After Ischemic Stroke by Danhong Injection. Mol Neurobiol 60, 413–427 (2023). https://doi.org/10.1007/s12035-022-03075-z

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