2. Academic Validation
  3. Activation of the PERK Branch of the UPR as a Strategy for Improving Outcomes in Acute Ischemic Stroke

Activation of the PERK Branch of the UPR as a Strategy for Improving Outcomes in Acute Ischemic Stroke

  • ACS Omega. 2025 Apr 7;10(15):15461-15470. doi: 10.1021/acsomega.5c00125.
Xiangzhu Li 1 2,  Dongting Lu 3,  Lei Zou 1,  Lijuan Ma 4 5,  Yukun Yang 6,  Xingyun Quan 6,  Wei Song 7,  Qinlian Ye 1,  Hui-Lun Lu 8,  Ulf Brockmeier 6,  Yanxia Zhou 9,  Guodong Huang 1,  Ya-Chao Wang 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Institute Translational Medicine, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
  • 2 Shenzhen Traditional Chinese Medicine Hospital, No. 1, Fuhua Road, Futian District, Shenzhen 518033, Guangdong, China.
  • 3 Department of Neurology, Guangxi University of Chinese Medicine, Nanning 530200, China.
  • 4 The Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Key Laboratory of Laparoscopic Technology, the First Affiliated Hospital of Shandong First Medical University, Shandong 250014, China.
  • 5 Hisense Postdoctoral Research Station, No. 399 Songling Road, Laoshan District, Qingdao 266100, Shandong, China.
  • 6 Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany.
  • 7 Nanophotonics Research Center, Shenzhen Key Laboratory of Micro-Scale Optical Information Technology, Institute of Microscale Optoelectronics, Shenzhen University, Shenzhen 518060, China.
  • 8 Department of Respiratory Medicine, The Second Peoples Hospital of Longgang District, Shenzhen 518112, China.
  • 9 Department of Neurology, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
PMID: 40290914 DOI: 10.1021/acsomega.5c00125
Abstract

Brain ischemia disrupts endoplasmic reticulum (ER) dynamics, causes ER stress, and triggers the unfolded protein response (UPR). During the UPR, protein kinase RNA-like ER kinase (PERK) phosphorylates eIF2α, shutting down global protein synthesis, inhibits protein synthesis, and provides neuroprotection during acute ischemic stroke. Herein, middle cerebral artery occlusion/reperfusion (MCAO/R) and PERK neuron-specific deletion conditional knockout mice were employed to observe the function and mechanisms of PERK. CCT020312, a novel selective PERK activator, specifically activates PERK and provides neuroprotection both in vivo and in vitro stroke models. Additionally, CCT020312 enhanced neuronal survival and cerebral microvessels and decreased the level of astrogliosis in acute ischemic stroke mice. Furthermore, in vivo experiments demonstrated that CCT020312 not only prevented Apoptosis but also enhanced the PERK/p-eIF2α/LC3-II Autophagy signaling pathway in MCAO/R mice. In conclusion, our study supports the potential therapeutic value of targeting PERK in acute ischemic stroke, offering a promising strategy for enhancing stroke outcomes through the modulation of protein synthesis and the Autophagy pathway.

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