2. Academic Validation
  3. Evodiamine inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy

Evodiamine inhibits NLRP3 inflammasome-mediated microglial pyroptosis and promotes remyelination via SLC2A4-regulated autophagy

  • Phytomedicine. 2025 Jul 25:143:156866. doi: 10.1016/j.phymed.2025.156866.
Yunjie Zhao 1,  Xingzong Sun 1,  Faling Shao 1,  Lin Li 1,  Weilie Xiao 1,  Chengyang Gu 1,  Yunqian Zhang 1,  Yue Jia 2,  Lili Dai 3,  Hongliang Li 4,  Hongkun Bao 5
Affiliations

Affiliations

  • 1 School of Medicine, School of Pharmacy, Yunnan University, 2 Cuihu North Road, Kunming, Yunnan 650091, China.
  • 2 Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming 650118, China.
  • 3 School of Agronomy and Life Sciences, Kunming University, Kunming 650214, China. Electronic address: victory167@126.com.
  • 4 School of Medicine, School of Pharmacy, Yunnan University, 2 Cuihu North Road, Kunming, Yunnan 650091, China. Electronic address: lihongliang@ynu.edu.cn.
  • 5 School of Medicine, School of Pharmacy, Yunnan University, 2 Cuihu North Road, Kunming, Yunnan 650091, China. Electronic address: baohongkun@ynu.edu.cn.
PMID: 40393245 DOI: 10.1016/j.phymed.2025.156866
Abstract

Background: Activation of the NLRP3 inflammasome triggers Pyroptosis, a pro-inflammatory type of cell death, in multiple sclerosis (MS). Evodiamine (EVO) possesses anti-inflammatory and neuroprotective properties; however, its potential molecular and signaling pathways in MS remain to be elucidated. This study aimed to explore the therapeutic potential of EVO for remyelination in MS and elucidated its underlying mechanisms.

Methods: We utilized cuprizon (CPZ)/experimental autoimmune encephalomyelitis (EAE)-induced demyelinated mice and lipopolysaccharide+adenosine triphosphate (LPS+ATP)-induced Pyroptosis of BV2 cells to investigate the potential of EVO in MS treatment. Various analyses were conducted, including rotarod fatigue test, RNA sequence, luxol fast blue, molecular docking, SPR, immunoblotting, qRT-PCR, immunofluorescence, and transmission electron microscopy, to analysis the targets and signaling pathways involved in EVO treatment.

Results: EVO emerged as a promising remyelination agent in the CPZ/EAE demyelination models, acting through SLC2A4. Regarding its mechanism, EVO inhibited NLRP3 inflammasome-mediated microglial Pyroptosis through SLC2A4 regulation of Autophagy during demyelinating disease, but this change was reversed by SLC2A4 inhibitor PGF2α in vivo. Additionally, EVO inhibited LPS+ATP-induced Pyroptosis of BV2 cells by preventing NLRP3 inflammasome activity and cleavage of the Pyroptosis executive protein gasdermin D. It also promoted Autophagy and inhibited NLRP3 inflammasome-mediated Pyroptosis in BV2 cells via SLC2A4. Furthermore, an Autophagy inhibitor 3-methyladenine reversed the inhibitory effect of EVO on NLRP3 inflammasome-mediated Pyroptosis in BV2 cells.

Conclusion: The present study demonstrated that EVO inhibits NLRP3 inflammasome-mediated microglial Pyroptosis and promotes remyelination via SLC2A4-regulated Autophagy during demyelinating disease, which suggests EVO as a promising drug candidate for the treatment of MS.

Keywords

Autophagy; Evodiamine; NLRP3 inflammasome; Pyroptosis; SLC2A4.

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