2. Academic Validation
  3. SIRT2-mediated autophagy as a target of butylphthalide in the treatment of ischemic stroke

SIRT2-mediated autophagy as a target of butylphthalide in the treatment of ischemic stroke

  • Biochem Biophys Res Commun. 2025 Oct 1:783:152588. doi: 10.1016/j.bbrc.2025.152588.
Hai-Qian Zhou 1,  Hai-Tao Gao 1,  Wen-Mei Lu 1,  Wen-Liang Jiang 2,  Dan-Hong Wu 3
Affiliations

Affiliations

  • 1 Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China; Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240 China; Center of Community-Based Health Research, Fudan University, Shanghai 200032, China.
  • 2 Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240 China; Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, Affiliated Mental Health Center, School of Life Science, East China Normal University, Shanghai, 200062, China.
  • 3 Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China; Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240 China; Center of Community-Based Health Research, Fudan University, Shanghai 200032, China. Electronic address: danhongwu@fudan.edu.cn.
PMID: 40934558 DOI: 10.1016/j.bbrc.2025.152588
Abstract

Sirtuin-2 (SIRT2) is an NAD+-dependent deacetylase that has been implicated in neuronal stress responses. The present study investigates the hypothesis that SIRT2 directly regulates LC3B acetylation under ischemic-like conditions, and that dl-3-n-butylphthalide (NBP) modulates this axis. In SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), SIRT2 and the LC3B-II/I ratio increased, indicating Autophagy activation. It was demonstrated that NBP was capable of restoring cell viability and normalizing SIRT2 and LC3B-II/I levels. Co-immunoprecipitation revealed the existence of an endogenous SIRT2-LC3B complex; SIRT2 overexpression resulted in a reduction of acetyl-LC3B, whereas the SIRT2 Inhibitor AK-7 elevated LC3B-II/I. Molecular docking (AutoDock Vina) predicted stable NBP binding to the SIRT2 catalytic pocket, a prediction that was supported by 100-ns AMBER simulations (stable RMSD) and favorable binding free energy. The knockdown of SIRT2 resulted in the abrogation of the changes in LC3B-II/I that were driven by OGD/R- and NBP-, indicating a dependence on SIRT2. The findings of this study lend further support to the hypothesis that SIRT2 functions as an LC3B deacetylase under conditions of ischemic stress and suggest that NBP exerts its protective effect, at least in part, through the inhibition of SIRT2, thereby facilitating the normalization of Autophagy.

Keywords

Autophagy; Deacetylation; Ischemic stroke; LC3B; SIRT2.

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