2. Academic Validation
  3. Gastrodin promotes Alkbh5 nuclear localization and Gclm m6A demethylation to alleviate ferroptosis in ischemic stroke

Gastrodin promotes Alkbh5 nuclear localization and Gclm m6A demethylation to alleviate ferroptosis in ischemic stroke

  • Phytomedicine. 2025 Aug 16:147:157177. doi: 10.1016/j.phymed.2025.157177.
Jinsha Shi 1,  Xiao Xiao 2,  Zhao Wang 1,  Xinglin Zhang 1,  Xianfeng Kuang 1,  Shuhan Yang 1,  Hanjun Zuo 1,  Tao Guo 1,  Rong Xiao 1,  Yue Li 3,  Yundan Liang 4,  Linbo Gao 5,  Juanjuan Li 6
Affiliations

Affiliations

  • 1 Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming 650500, PR China.
  • 2 Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; NHC Key Laboratory of Chronobiology (Sichuan University); Children's Medicine Key Laboratory of Sichuan Province; West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 3 Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, Sichuan 610500, PR China.
  • 4 Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, Sichuan 610500, PR China. Electronic address: 102016056@cmc.edu.cn.
  • 5 Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education; NHC Key Laboratory of Chronobiology (Sichuan University); Children's Medicine Key Laboratory of Sichuan Province; West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: gaolinbo@scu.edu.cn.
  • 6 Department of Anatomy and Histology & Embryology, School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming 650500, PR China. Electronic address: lijuanjuan@kmmu.edu.cn.
PMID: 40839993 DOI: 10.1016/j.phymed.2025.157177
Abstract

Background: Ischemic stroke (IS) remains a major contributor to global morbidity and mortality, largely due to limited therapies and unclear pathogenesis. Gastrodin (GAS), a bioactive ingredient from traditional Chinese medicine, has shown potential in mitigating Apoptosis, inflammation, and Pyroptosis. Recent research highlights Ferroptosis as a crucial factor in IS development.

Purpose: In this study, we aimed to examine the effect and mechanism of GAS on Ferroptosis in IS.

Methods: Mendelian randomization (MR) was applied to evaluate the effect of GAS on IS risk. The neuroprotective and anti-ferroptotic effects of GAS were assessed through TTC staining, neurological deficit scoring, and detection of ferroptosis-related biomarkers. GAS target was predicted via network pharmacology and molecular docking, and validated using surface plasmon resonance and cellular thermal shift assay. Phosphorylation, nuclear translocation, and N⁶-methyladenosine methylation were analyzed using Western blotting, immunofluorescence, and MeRIP-qPCR.

Results: MR analyses identified a negative association between GAS and IS. GAS treatments attenuated cerebral infarct volume, improved neurological function, and alleviated Ferroptosis both in vivo and in vitro. Mechanistically, GAS binds to PI3K, activating the PI3K/Akt signaling pathway through phosphorylation. Phosphorylated Akt induces serine/threonine phosphorylation and nuclear translocation of Alkbh5, which reduces the m6A methylation levels of glutamate-cysteine Ligase modifier subunit (Gclm), resulting in increased Gclm expression and enhanced GSH synthesis, and ultimately contributing to the inhibition of Ferroptosis in IS.

Conclusion: This study is the first to demonstrate that GAS mitigates IS-induced Ferroptosis via the PI3K/Akt-Alkbh5-Gclm axis, bridging epigenetic regulation and iron metabolism.

Keywords

Ferroptosis; Gastrodin; Ischemic stroke; PI3K/Akt/Alkbh5/Gclm.

Figures
Products
Inhibitors & Agonists
Other Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z