2. Academic Validation
  3. Moracin N alleviates ischaemic brain injury in mice by suppressing neuronal ferroptosis via the activation of the Keap1/Nrf2 signalling pathway

Moracin N alleviates ischaemic brain injury in mice by suppressing neuronal ferroptosis via the activation of the Keap1/Nrf2 signalling pathway

  • Phytomedicine. 2025 Sep 12:148:157253. doi: 10.1016/j.phymed.2025.157253.
Jianbin Zhang 1,  Qian Xia 2,  Gaofeng Zhan 2,  Xue Zhang 2,  Shuai Gao 3,  Tangrui Han 3,  Yilin Zhao 4,  Xing Li 5,  Yonghong Wang 6
Affiliations

Affiliations

  • 1 Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan 030053, China.
  • 2 Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 Department of Neurosurgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China.
  • 4 Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: yilinzhao@hust.edu.cn.
  • 5 Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: lixing88@hust.edu.cn.
  • 6 Department of Neurosurgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China. Electronic address: wyh200533@126.com.
PMID: 40972263 DOI: 10.1016/j.phymed.2025.157253
Abstract

Background: Emerging evidence suggests that oxidative stress-induced lipid peroxidation ultimately results in Ferroptosis, which contributes to the progression of ischaemic brain injury. Moracin N is a leading chemical purified from mulberry leaves. Previous studies have reported that moracin N has good antioxidant activity. However, the specific impact of moracin N on ischaemic stroke have not been determined.

Purpose: The present research sought to investigate the neuroprotective effects and mechanisms by which moracin N protects against Ferroptosis after ischaemic stroke.

Methods: An animal model of ischaemic stroke was established via middle cerebral artery occlusion (MCAO) in mice. Mice received moracin N (20 mg·kg-1·d-1) via intracerebroventricular injection for three days before the start of reperfusion.

Results: Moracin N treatment reduced the brain infarct volume and water content, attenuated neurological deficit scores, and improved long-term neurological function recovery in a mouse model of ischaemic stroke (p < 0.05). Moreover, moracin N treatment prevented Ferroptosis in the brains of MCAO mice and in primary neurons challenged with oxygen-glucose deprivation in vitro by downregulating FTH1 and ACSL4 and increasing glutathione synthesis (p < 0.05). Mechanistic studies revealed that moracin N increased the activation of the Keap1/Nrf2 signalling pathway. Finally, the neuroprotective effects of moracin N were blocked by the use of ML385, an Nrf2 inhibitor, as evidenced by the excessive iron accumulation and deactivation of the Ferroptosis defence system (p < 0.05).

Conclusions: Moracin N suppresses oxidative stress-induced neuronal cell death after ischaemic stroke by inhibiting Ferroptosis via the Keap1/Nrf2 signalling pathway, indicating that it could serve as a potential therapeutic candidate for cerebral ischaemia.

Keywords

Ferroptosis; Ischemic brain injury; Keap1; Moracin N; Nrf2; Oxidative stress.

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