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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Exploring the Neuroprotective Effects of Walnut (Juglans regia L.) Against Cognitive Impairment in Alzheimer’s Disease Through the MAPK-mTORC1-TFEB-Mediated Endolysosomal Pathway: A Network Pharmacology and Molecular Docking Approach

  • Chih-Ting Lin1,2,3
  • Kuan-Tso Chen1,3
  • Yu-Chiang Hung4,5
5 affiliations
  1. 1Department of Chinese Medicine, E-Da Cancer Hospital, Kaohsiung 82445, Taiwan
  2. 2Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
  3. 3School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung 84001, Taiwan
  4. 4Department of Chinese Medicine, Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
  5. 5Linsen Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei 10450, Taiwan
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Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis. Given the clinical need for multi-target interventions, this study elucidated the neuroprotective mechanisms of walnut (Juglans regia L.) against AD-related cognitive impairment. Methods: We characterized 25 bioactive constituents (fatty acids and ellagitannins) and constructed a protein–protein interaction (PPI) network. GO/KEGG enrichment, integrated with Ingenuity Pathway Analysis (IPA), deciphered pharmacological pathways, followed by molecular docking to evaluate ligand–target binding thermodynamics. Network analysis revealed that walnut phytochemicals synergistically modulate the MAPK-mTORC1-TFEB-mediated endolysosomal homeostasis pathway. Molecular docking indicated that ellagitannins (strictinin, pedunculagin, tellimagrandin I) exhibit robust affinities for upstream RAS/RAF/MEK kinases, suppressing pro-pathogenic signaling. Concurrently, gallic acid targeted ABCA1 and TFEB, promoting TFEB activation and nuclear translocation to enhance beta-amyloid clearance and lysosomal biogenesis. This study provides evidence that walnut attenuates AD pathology through “multi-component” reinforcement of the endolysosomal defense system, establishing a mechanistic foundation for walnut as a promising functional food.

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Cite

BibTeXRIS
BibTeX
@article{lin2026exploring,
  title = {{Exploring the Neuroprotective Effects of Walnut (Juglans regia L.) Against Cognitive Impairment in Alzheimer’s Disease Through the MAPK-mTORC1-TFEB-Mediated Endolysosomal Pathway: A Network Pharmacology and Molecular Docking Approach}},
  author = {Chih-Ting Lin and Kuan-Tso Chen and Yu-Chiang Hung},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = sep,
  doi = {10.3390/ijms27188288},
  url = {https://www.mdpi.com/1422-0067/27/18/8288},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Exploring the Neuroprotective Effects of Walnut (Juglans regia L.) Against Cognitive Impairment in Alzheimer’s Disease Through the MAPK-mTORC1-TFEB-Mediated Endolysosomal Pathway: A Network Pharmacology and Molecular Docking Approach
AU  - Chih-Ting Lin
AU  - Kuan-Tso Chen
AU  - Yu-Chiang Hung
PY  - 2026
DA  - 2026/09/17
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27188288
UR  - https://www.mdpi.com/1422-0067/27/18/8288
AB  - Alzheimer’s disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis. Given the clinical need for multi-target interventions, this study elucidated the neuroprotective mechanisms of walnut (Juglans regia L.) against AD-related cognitive impairment. Methods: We characterized 25 bioactive constituents (fatty acids and ellagitannins) and constructed a protein–protein interaction (PPI) network. GO/KEGG enrichment, integrated with Ingenuity Pathway Analysis (IPA), deciphered pharmacological pathways, followed by molecular docking to evaluate ligand–target binding thermodynamics. Network analysis revealed that walnut phytochemicals synergistically modulate the MAPK-mTORC1-TFEB-mediated endolysosomal homeostasis pathway. Molecular docking indicated that ellagitannins (strictinin, pedunculagin, tellimagrandin I) exhibit robust affinities for upstream RAS/RAF/MEK kinases, suppressing pro-pathogenic signaling. Concurrently, gallic acid targeted ABCA1 and TFEB, promoting TFEB activation and nuclear translocation to enhance beta-amyloid clearance and lysosomal biogenesis. This study provides evidence that walnut attenuates AD pathology through “multi-component” reinforcement of the endolysosomal defense system, establishing a mechanistic foundation for walnut as a promising functional food.
SN  - 1422-0067
ER  -