Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (1): 333-345.doi: 10.4103/NRR.NRR-D-24-00044

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Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress

Yumei Liao1, 2, 3, #, Qinghua Zhang3, #, Qiaoyun Shi3, #, Peng Liu2, 3, Peiyun Zhong3 , Lingling Guo2, 3, Zijian Huang2, 3, Yinghui Peng2, 3, Wei Liu4 , Shiqing Zhang2, 3, István Adorján5 , Yumi Fukuzaki6 , Eri Kawashita7 , Xiao-Qi Zhang2, 3, Nan Ma2, *, Xiaoshen Zhang1, 8, *, Zoltán Molnár9, *, Lei Shi1, 2, 3, *   

  1. 1 Department of Cardiovascular Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, China;  2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, Guangdong Province, China;  3 JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, Guangdong Province, China;  4 Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute; Institute of Geriatric Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong Province, China;  5 Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary;  6 Department of Neurology, University of California, San Francisco, San Francisco, CA, USA;  7 Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan;  8 School of Nursing, Jinan University, Guangzhou, Guangdong Province, China;  9 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
  • Online:2026-01-15 Published:2025-04-24
  • Contact: Nan Ma, PhD, nanma927@126.com; Xiaoshen Zhang, MD, PhD, xsh.zhang@hotmail.com; Zoltán Molnár, MD, DPhil, zoltan.molnar@dpag.ox.ac.uk; Lei Shi, PhD, t_shilei@jnu.edu.cn or sophielshi80@gmail.com.
  • Supported by:
    This study was supported in part by the National Key Research & Development Program of China, No. 2022YFA1104900 (to LS); the National Natural Science Foundation of China, Nos. 82371175, 82071535 (both to LS), 82101614 (to YP); the International Science and Technology Cooperation Projects of Guangdong Province, No. 2023A0505050121 (to LS); Guangdong Basic and Applied Basic Research Foundation, Nos. 2022B1515130007 (to LS), 2023A1515030012 (to SZ), 2022A1515010666 (to WL); the Science and Technology Program of Guangzhou, Nos. 202102070001 (to LS), 202201010041 (to YP); and Shenzhen Basic Research Grant, Nos. JCYJ20200109140414636, JCYJ20230807145103007 (both to WL). Lei Shi was awarded a Royal Society Newton Advanced Fellowship, No. AOMS-NAF0051003, in collaboration with Zoltán Molnár, Department of Physiology, Anatomy and Genetics, University of Oxford (2017–2021).

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Abstract: Neuroserpin, a secreted protein that belongs to the serpin superfamily of serine protease inhibitors, is highly expressed in the central nervous system and plays multiple roles in brain development and pathology. As a natural inhibitor of recombinant tissue plasminogen activator, neuroserpin inhibits the increased activity of tissue plasminogen activator in ischemic conditions and extends the therapeutic windows of tissue plasminogen activator for brain ischemia. However, the neuroprotective mechanism of neuroserpin against ischemic stroke remains unclear. In this study, we used a mouse model of middle cerebral artery occlusion and oxygen-glucose deprivation/reperfusion-injured cortical neurons as in vivo and in vitro ischemia-reperfusion models, respectively. The models were used to investigate the neuroprotective effects of neuroserpin. Our findings revealed that endoplasmic reticulum stress was promptly triggered following ischemia, initially manifesting as the acute activation of endoplasmic reticulum stress transmembrane sensors and the suppression of protein synthesis, which was followed by a later apoptotic response. Notably, ischemic stroke markedly downregulated the expression of neuroserpin in cortical neurons. Exogenous neuroserpin reversed the activation of multiple endoplasmic reticulum stress signaling molecules, the reduction in protein synthesis, and the upregulation of apoptotic transcription factors. This led to a reduction in neuronal death induced by oxygen/glucose deprivation and reperfusion, as well as decreased cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion. However, the neuroprotective effects of neuroserpin were markedly inhibited by endoplasmic reticulum stress activators thapsigargin and tunicamycin. Our findings demonstrate that neuroserpin exerts neuroprotective effects on ischemic stroke by suppressing endoplasmic reticulum stress.

Key words: endoplasmic reticulum stress, ischemia-reperfusion injury, neuron, neuronal apoptosis, neuroprotection, neuroserpin, protein synthesis, secretory protein, stroke, transcriptomic analysis