2. Academic Validation
  3. Piceatannol upregulates USP14-mediated GPX4 deubiquitination to inhibit neuronal ferroptosis caused by cerebral ischemia-reperfusion in mice

Piceatannol upregulates USP14-mediated GPX4 deubiquitination to inhibit neuronal ferroptosis caused by cerebral ischemia-reperfusion in mice

  • Food Chem Toxicol. 2025 Mar:197:115281. doi: 10.1016/j.fct.2025.115281.
Qiuju Zhao 1,  Xinya Wang 1,  Taiyu Zhang 1,  Shuxian Guo 1,  Xiaojia Liu 1,  Shihao Wan 1,  Yani Guo 1,  Qiannuo Zhang 1,  Jinshui Li 1,  Shaohua Wang 2,  Liuyi Dong 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology of Ministry of Education, Key Laboratory of Chinese Medicine Research and Development of State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, PR China.
  • 2 Department of Neurosurgery, Hefei Hospital Affiliated to Anhui Medical University, The Second People's Hospital of Hefei, Hefei, Anhui, PR China. Electronic address: Wangsh72622@163.com.
  • 3 Department of Pharmacology, Key Laboratory of Anti-Inflammatory and Immunopharmacology of Ministry of Education, Key Laboratory of Chinese Medicine Research and Development of State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei, Anhui, PR China. Electronic address: dongly@ahmu.edu.cn.
PMID: 39880152 DOI: 10.1016/j.fct.2025.115281
Abstract

Ischemic stroke is a very common brain disorder. This study aims to assess the neuroprotective effects of piceatannol (PCT) in preventing neuronal injury resulting from cerebral ischemia and reperfusion (I/R) in mice. Additionally, we investigated the underlying mechanisms through which PCT inhibits neuronal Ferroptosis by modulating the USP14/GPX4 signaling axis. In vitro and in vivo experiments were conducted. In vitro, oxygen-glucose deprivation followed by reoxygenation (OGD/R) was used to simulate ischemic injury in neuronal cells. We utilized various techniques, including DCFH-DA staining, FeRhoNox-1 staining, MDA and GSH determination, immunofluorescence, Western blotting, co-immunoprecipitation, plasmid and siRNA transfection, to evaluate the therapeutic efficacy of PCT and elucidate its mechanism of action. For vivo studies, we established a mouse model of I/R by ligating the bilateral common carotid arteries. The efficacy of PCT in mitigating brain injury and cognitive dysfunction were assessed through behavioral tests, histological analysis, Western blotting, and immunohistochemistry. PCT treatment significantly enhanced cell viability under OGD/R and reduced lipid peroxidation by decreasing levels of ROS, MDA. Furthermore, PCT effectively inhibited neuronal Ferroptosis by modulating the expression of key ferroptosis-related proteins, including GPX4, ACSL4, FPN1, and Ferritin. Mechanistically, PCT was found to prevent GPX4 degradation through USP14-mediated deubiquitination. Notably, silencing USP14 reversed the ferroptotic effects of PCT, whereas overexpressing of USP14 amplified these effects. In vivo, PCT significantly reduced pathological damage of brain tissue and improved cognitive dysfunction. Piceatannol exerts neuroprotective effects by regulating Ferroptosis through the USP14/GPX4 axis, thereby preventing cerebral ischemia/reperfusion injury.

Keywords

Cerebral-ischemia reperfusion; Deubiquitination; Ferroptosis; GPX4; Piceatannol.

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