2. Academic Validation
  3. Repurposing Lamivudine: A novel therapeutic strategy for ischemic stroke targeting the glycolytic enzyme Pgk1

Repurposing Lamivudine: A novel therapeutic strategy for ischemic stroke targeting the glycolytic enzyme Pgk1

  • Biochem Pharmacol. 2026 Jan;243(Pt 2):117529. doi: 10.1016/j.bcp.2025.117529.
Jingjing Liu 1,  Jia Kang 2,  Wenyang Zhao 2,  Jing Zhou 2,  Chun Li 2,  Tongyu Wu 2,  Liang Han 2,  Xinrui Meng 2,  Manfei Deng 3,  Youquan Gu 4,  Zhiqing Liu 5,  Xiaohua Liu 6,  Xinping Chen 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; School of Basic Medical Sciences, University of South China, Hengyang, Hunan 421001, PR China. Electronic address: [email protected].
  • 2 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
  • 3 School of Basic Medical Sciences, University of South China, Hengyang, Hunan 421001, PR China.
  • 4 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; Department of Neurology, First Hospital of Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 5 Institute of Evolution & Marine Biodiversity, Ocean University of China, 266000, PR China. Electronic address: [email protected].
  • 6 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 7 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou 730000, PR China; Southeast Research Institute, Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
PMID: 41213407 DOI: 10.1016/j.bcp.2025.117529
Abstract

Cerebral ischemic stroke, characterized by high mortality and morbidity, poses significantly challenges due to extensive neuronal cell death. To discover new cell death inhibitors suitable for clinical application, we screened chemicals and found lamivudine prevented cell death rendered by oxidative stress and oxygen glucose deprivation/re-oxygenation (OGD/R) injury. Remarkably, lamivudine reduced infarct volume at doses much lower than those used in Antiviral treatments. It activates phosphoglycerate kinase 1 (Pgk1), increasing p-AKT level to suppress Bcl-2/Bax-mediated Apoptosis and Cas-1/GSDMD-mediated Pyroptosis, finally boosting cell viability under multiple stresses. Work on gain- and loss-of-function of Pgk1 further validated its role as a target of lamivudine and the major player in the pathogenesis of cerebral ischemic stroke. Moreover, overexpression of Pgk1 by Adeno-Associated Virus (AAVs) reduced the neuronal deficits, cerebral infarction volumes, and histopathology changes in the rats experiencing cerebral ischemia-reperfusion (I/R) injury. In summary, lamivudine stimulates Pgk1 to enhance the critical survival pathway to ramp down both Apoptosis and Pyroptosis to improve ischemic stroke, that would facilitate translation of lamivudine into new medicine against the fatal disease.

Keywords

Apoptosis; Ischemic stroke; Lamivudine; Pgk1; Pyroptosis.

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