Avicularin inhibits ferroptosis and improves cognitive impairments in Alzheimer's disease by modulating the NOX4/Nrf2 axis

Zixiang Li; Yingying Lu; Yongqi Zhen; Wenke Jin; Xuelan Ma; Ziyue Yuan; Bo Liu; Xian-Li Zhou; Lan Zhang

doi:10.1016/j.phymed.2024.156209

Avicularin inhibits ferroptosis and improves cognitive impairments in Alzheimer's disease by modulating the NOX4/Nrf2 axis

Phytomedicine. 2024 Oct 31:135:156209. doi: 10.1016/j.phymed.2024.156209. Online ahead of print.

Authors

Zixiang Li¹, Yingying Lu², Yongqi Zhen³, Wenke Jin², Xuelan Ma⁴, Ziyue Yuan², Bo Liu⁵, Xian-Li Zhou⁶, Lan Zhang⁷

Affiliations

¹ Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China; Key Laboratory of Advanced Technologies of Material, Minister of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
² Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
³ Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
⁵ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. Electronic address: [email protected].
⁶ Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China. Electronic address: [email protected].
⁷ Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China. Electronic address: [email protected].

PMID: 39515096
DOI: 10.1016/j.phymed.2024.156209

Abstract

Background: Alzheimer's disease (AD) is a widespread neurodegenerative disorder for which effective therapies remain elusive, primarily due to the complexity of its underlying pathophysiology. In recent years, natural products have gained attention for their therapeutic potential in AD, owing to their multi-targeted actions and low toxicity profiles. Avicularin (Avi), a flavonoid derived from the peels of Zanthoxylum bungeanum Maxim., has shown promise as an anti-AD agent. However, the specific mechanisms by which Avi mitigates oxidative stress and inhibits ferroptosis in AD models remain insufficiently understood. Further investigation is required to elucidate its therapeutic potential in these pathways.

Purpose: Therefore, this study aims to elucidate the neuroprotective effects of Avi in AD by investigating its impact on the NOX4/Nrf2 signaling pathway, as well as its role in modulating oxidative stress and ferroptosis.

Methods: In this study, an in vitro H₂O₂-induced oxidative stress model in SH-SY5Y cells was utilized to evaluate the pharmacological efficacy and underlying mechanisms of Avi. Molecular docking, cellular thermal shift assay and bio-layer interferometry assays were conducted to identify potential molecular targets of Avi. Additionally, in vivo models, including scopolamine (SCOP)-induced and APP/PS1 transgenic mice, were employed to assess the cognitive effects of Avi and further explore its associated molecular mechanisms.

Results: Our study demonstrates that Avi effectively attenuates H₂O₂-induced toxicity in SH-SY5Y cells by reducing apoptosis and enhancing cellular antioxidant defenses. This neuroprotective effect is mediated through the inhibition of NOX4 and the promotion of Nrf2 nuclear translocation. Furthermore, Avi improves cognitive function and mitigates ferroptosis in both SCOP-induced and APP/PS1 transgenic mouse models of AD.

Conclusion: Avi emerges as an effective neuroprotective agent against AD, offering a promising therapeutic approach by targeting the NOX4/Nrf2 signaling axis to alleviate oxidative stress and ferroptosis.

Keywords: Alzheimer's disease; Avicularin; Ferroptosis; NOX4/Nrf2 axis; Zanthoxylum bungeanum Maxim..