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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Gastrodin and Microglial Autophagy–Pyroptosis Crosstalk: Evidence and Hypotheses Involving the AMPK/mTOR/NLRP3 Axis

  • Chan-Yen Kuo1
  • I-Shiang Tzeng2
  • Yi-Chyan Chen3
  • Mao-Liang Chen2
  1. 1Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan
  2. 2Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231016, Taiwan
  3. 3Department of Psychiatry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231016, Taiwan
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Abstract

Gastrodin (GAS), a bioactive glycoside from Gastrodia elata, shows anti-inflammatory and neuroprotective activity in preclinical models. This narrative review evaluates whether autophagy, mitochondrial quality control, and NOD-like receptor family pyrin domain containing 3 (NLRP3)-dependent pyroptosis may contribute to its effects on microglia. Studies in microglial cultures and animal models report reduced inflammatory activation and changes in microglial phenotype after GAS treatment. Related studies in endothelial cells, neurons, macrophages, and whole brain tissue associate GAS with AMP-activated protein kinase (AMPK) signaling, mechanistic target of rapamycin (mTOR) inhibition, autophagy or mitophagy markers, and lower inflammasome or pyroptosis markers. These findings support an AMPK/mTOR/NLRP3-centered working model, but the complete causal chain has not been demonstrated in microglia within a single experimental system. We distinguish microglia-specific observations from evidence extrapolated across cell types and disease models, compare GAS with its metabolite p-hydroxybenzyl alcohol, and discuss limitations of inhibitor-based experiments and variation in dose and sampling time. Inducible microglial genetic deletion, flux measurements, target-engagement assays, and matched pharmacokinetic studies are needed to test this model. Human evidence remains insufficient to confirm the proposed microglial mechanism or its clinical relevance.

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Cite

BibTeXRIS
BibTeX
@article{kuo2026gastrodin,
  title = {{Gastrodin and Microglial Autophagy–Pyroptosis Crosstalk: Evidence and Hypotheses Involving the AMPK/mTOR/NLRP3 Axis}},
  author = {Chan-Yen Kuo and I-Shiang Tzeng and Yi-Chyan Chen and Mao-Liang Chen},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = sep,
  doi = {10.3390/ijms27198754},
  url = {https://www.mdpi.com/1422-0067/27/19/8754},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Gastrodin and Microglial Autophagy–Pyroptosis Crosstalk: Evidence and Hypotheses Involving the AMPK/mTOR/NLRP3 Axis
AU  - Chan-Yen Kuo
AU  - I-Shiang Tzeng
AU  - Yi-Chyan Chen
AU  - Mao-Liang Chen
PY  - 2026
DA  - 2026/09/30
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27198754
UR  - https://www.mdpi.com/1422-0067/27/19/8754
AB  - Gastrodin (GAS), a bioactive glycoside from Gastrodia elata, shows anti-inflammatory and neuroprotective activity in preclinical models. This narrative review evaluates whether autophagy, mitochondrial quality control, and NOD-like receptor family pyrin domain containing 3 (NLRP3)-dependent pyroptosis may contribute to its effects on microglia. Studies in microglial cultures and animal models report reduced inflammatory activation and changes in microglial phenotype after GAS treatment. Related studies in endothelial cells, neurons, macrophages, and whole brain tissue associate GAS with AMP-activated protein kinase (AMPK) signaling, mechanistic target of rapamycin (mTOR) inhibition, autophagy or mitophagy markers, and lower inflammasome or pyroptosis markers. These findings support an AMPK/mTOR/NLRP3-centered working model, but the complete causal chain has not been demonstrated in microglia within a single experimental system. We distinguish microglia-specific observations from evidence extrapolated across cell types and disease models, compare GAS with its metabolite p-hydroxybenzyl alcohol, and discuss limitations of inhibitor-based experiments and variation in dose and sampling time. Inducible microglial genetic deletion, flux measurements, target-engagement assays, and matched pharmacokinetic studies are needed to test this model. Human evidence remains insufficient to confirm the proposed microglial mechanism or its clinical relevance.
SN  - 1422-0067
ER  -