Cardamonin attenuates SH-SY5Y neuronal apoptosis induced by LPS-activated microglia via modulation of the EGFR/PI3K/AKT1/ERK/NF-κB pathway
- 1Key Laboratory of Psychiatry, Huzhou Third Municipal Hospital, The Affiliated Hospital of Huzhou Normal University
- 2Sleep Medical Center, Huzhou Third Municipal Hospital, The Affiliated Hospital of Huzhou University
- 3Department of Pharmacology, School of Pharmacy, Nantong University
Abstract
Introduction: Microglial activation-induced neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases. Cardamonin (CD, 2′,4′-dihydroxy-6′-methoxychalcone), a natural chalcone flavonoid present in several medicinal plants, demonstrates significant anti-inflammatory activity. Nevertheless, the precise mechanisms by which it mitigates neuroinflammation remain incompletely understood.
Methods: In this study, the potential targets and pathways of CD were investigated using network pharmacology and molecular docking. The neuroinflammatory protective mechanisms were examined in vitro using LPS-stimulated BV2 cells and a BV2/SH-SY5Y co-culture system, employing ELISA, RT-qPCR, Western blot, immunofluorescence, and other assays.
Results and Discussion: Network pharmacology identified epidermal growth factor receptor (EGFR), rac-alpha serine/threonine-protein kinase (AKT1), heat shock protein 90 alpha family class B member 1 (HSP90AB1), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2) and transcription factor p65 (RELA) as key potential targets, with the EGFR/PI3K/AKT1, MAPK/ERK, and NF-κB signaling pathways being the main enriched pathways. In BV2 cells, CD suppressed LPS-induced production of IL-6, IL-1β, TNF-α, and nitric oxide (NO), and modulated the EGFR/PI3K/AKT1/ERK/NF-κB signaling axis. Pharmacological inhibition of EGFR or PI3K phenocopied the effects of CD, supporting the functional involvement of this pathway. Additionally, CD attenuated reactive oxygen species (ROS) accumulation and prevented the loss of mitochondrial membrane potential. In a co-culture model, CD pretreatment reduced BV2-conditioned medium neurotoxicity toward SH-SY5Y neurons. Collectively, these findings suggest that CD alleviates neuroinflammation through modulation of the EGFR/PI3K/AKT1/ERK/NF-κB pathway, mitigating inflammatory and oxidative stress responses and providing indirect neuroprotection, supporting its potential application in neuroinflammation-associated neurodegenerative diseases.
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BibTeX
@article{lu2026cardamonin,
title = {{Cardamonin attenuates SH-SY5Y neuronal apoptosis induced by LPS-activated microglia via modulation of the EGFR/PI3K/AKT1/ERK/NF-κB pathway}},
author = {Jingjing Lu and Rong Zhou and Kechao Tang and Hangwei Wang and Zhongxia Shen and Chao Huang and Lijun Cui},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1832453},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1832453/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cardamonin attenuates SH-SY5Y neuronal apoptosis induced by LPS-activated microglia via modulation of the EGFR/PI3K/AKT1/ERK/NF-κB pathway
AU - Jingjing Lu
AU - Rong Zhou
AU - Kechao Tang
AU - Hangwei Wang
AU - Zhongxia Shen
AU - Chao Huang
AU - Lijun Cui
PY - 2026
DA - 2026/10/19
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1832453
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1832453/full
AB - Introduction: Microglial activation-induced neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases. Cardamonin (CD, 2′,4′-dihydroxy-6′-methoxychalcone), a natural chalcone flavonoid present in several medicinal plants, demonstrates significant anti-inflammatory activity. Nevertheless, the precise mechanisms by which it mitigates neuroinflammation remain incompletely understood. Methods: In this study, the potential targets and pathways of CD were investigated using network pharmacology and molecular docking. The neuroinflammatory protective mechanisms were examined in vitro using LPS-stimulated BV2 cells and a BV2/SH-SY5Y co-culture system, employing ELISA, RT-qPCR, Western blot, immunofluorescence, and other assays. Results and Discussion: Network pharmacology identified epidermal growth factor receptor (EGFR), rac-alpha serine/threonine-protein kinase (AKT1), heat shock protein 90 alpha family class B member 1 (HSP90AB1), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2) and transcription factor p65 (RELA) as key potential targets, with the EGFR/PI3K/AKT1, MAPK/ERK, and NF-κB signaling pathways being the main enriched pathways. In BV2 cells, CD suppressed LPS-induced production of IL-6, IL-1β, TNF-α, and nitric oxide (NO), and modulated the EGFR/PI3K/AKT1/ERK/NF-κB signaling axis. Pharmacological inhibition of EGFR or PI3K phenocopied the effects of CD, supporting the functional involvement of this pathway. Additionally, CD attenuated reactive oxygen species (ROS) accumulation and prevented the loss of mitochondrial membrane potential. In a co-culture model, CD pretreatment reduced BV2-conditioned medium neurotoxicity toward SH-SY5Y neurons. Collectively, these findings suggest that CD alleviates neuroinflammation through modulation of the EGFR/PI3K/AKT1/ERK/NF-κB pathway, mitigating inflammatory and oxidative stress responses and providing indirect neuroprotection, supporting its potential application in neuroinflammation-associated neurodegenerative diseases.
SN - 1663-9812
ER -