2. Academic Validation
  3. Berberine alleviates Alzheimer's disease by activating autophagy and inhibiting ferroptosis through the JNK-p38MAPK signaling pathway

Berberine alleviates Alzheimer's disease by activating autophagy and inhibiting ferroptosis through the JNK-p38MAPK signaling pathway

  • Int Immunopharmacol. 2025 May 16:155:114550. doi: 10.1016/j.intimp.2025.114550.
Chunbin Sun 1,  Xiaoyu Gao 1,  Shuang Sha 1,  Si Wang 2,  Yubang Shan 1,  Luping Li 1,  Cencan Xing 3,  Hongyan Guan 4,  Hongwu Du 5
Affiliations

Affiliations

  • 1 School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China.
  • 2 The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China.
  • 3 School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083,China. Electronic address: cencanxing@ustb.edu.cn.
  • 4 China Testing & Certification International Group Co., Ltd., Beijing 100024, China. Electronic address: guanhongyan@ctc.ac.cn.
  • 5 School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China; Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083,China. Electronic address: hongwudu@ustb.edu.cn.
PMID: 40215776 DOI: 10.1016/j.intimp.2025.114550
Abstract

Introduction: Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposition, phosphorylated Tau Protein aggregation, inflammation, and neuronal damage. Neuronal Autophagy plays an important role in ameliorating central nervous system diseases such as AD. As an emerging form of iron-dependent cell death, Ferroptosis has attracted great attention in the field of neurodegenerative diseases. Berberine (BBR), a natural alkaloid, has demonstrated excellent in inflammation reduction, inhibition of Aβ production, and neuroprotection, making it a potential candidate for AD treatment. However, the mechanisms of Autophagy and Ferroptosis in BBR treatment of AD have not been elucidated.

Objectives: This study aimed to investigate the potential of BBR in alleviating AD and evaluate its molecular mechanism through a combination of network pharmacology and biological experiments.

Methods: We assessed alterations in Aβ plaques, neurons, neuroinflammation, and autophagy-related markers in the mice brain using immunofluorescence staining. Network pharmacology and molecular docking were used to analyze the potential targets and signaling pathways of BBR in the treatment of AD. Morris Water Maze (MWM) and new object recognition (NOR) experiments were used to test the spatial memory ability of mice. In addition, we validated the relationship between JNK-P38MAPK, Autophagy, Ferroptosis, and BBR treatment in 5xFAD mice and A β-induced SH-SY5Y cell models.

Results: The results of immunofluorescence staining showed that BBR effectively mitigated Aβ plaque deposition, ameliorated neuronal damage and neuroinflammation. The autophagy-related markers Beclin1 and LC3B were upregulated and p62 was downregulated after BBR treatment. The expression levels of ROS and lipid peroxide MDA decreased significantly after BBR treatment. qPCR results showed that the expression levels of ferroptosis-related genes TFR1, ASCL4, DMT1, and IREB2 were decreased, while the expression levels of FTH1 and SLC7A11 increased after BBR treatment. Behavioral experiments showed that BBR treatment enhanced spatial memory impairment in 5xFAD mice. Network pharmacological and in vitro analyses demonstrated that BBR activated Autophagy and inhibited Ferroptosis by inhibiting the JNK-P38MAPK signaling pathway. Following treatment with an Autophagy inhibitor on SH-SY5Y cells, Autophagy was markedly suppressed, and Ferroptosis was induced.

Conclusion: In summary, we found that BBR alleviates AD by inhibiting the JNK-P38MAPK pathway to enhance Autophagy and inhibit Ferroptosis, further reducing Aβ plaque deposition, inhibiting inflammatory response, and improving neuronal damage.

Keywords

Alzheimer's disease; Autophagy; Berberine; Ferroptosis; JNK-p38MAPK signaling pathway.

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