2. Academic Validation
  3. LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX

LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX

  • Redox Biol. 2024 Oct:76:103346. doi: 10.1016/j.redox.2024.103346.
Dongya Jiang 1,  Jing Zhao 2,  Jie Zheng 3,  Yingmin Zhao 4,  Meini Le 2,  Dani Qin 5,  Qiong Huang 2,  Jinyu Huang 6,  Qingshun Zhao 7,  Long Wang 8,  Xiaohua Dong 9
Affiliations

Affiliations

  • 1 Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 2 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, and Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
  • 4 Department of Pediatric, Jingjiang People's Hospital Affiliated to Yangzhou University, Jingjiang, China.
  • 5 Department of Pediatrics, Yixing People's Hospital, Yixing, China.
  • 6 Department of Cardiology, Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University.
  • 7 Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu, China. Electronic address: qingshun@nju.edu.cn.
  • 8 Department of Cardiology, Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University. Electronic address: wanglong@hospital.westlake.edu.cn.
  • 9 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: njfishxiaohua@163.com.
PMID: 39260063 DOI: 10.1016/j.redox.2024.103346
Abstract

Hypoxic-ischemic encephalopathy (HIE) poses a significant challenge in neonatal medicine, often resulting in profound and lasting neurological deficits. Current therapeutic strategies for hypoxia-ischemia brain damage (HIBD) remain limited. Ferroptosis has been reported to play a crucial role in HIE and serves as a potential therapeutic target. However, the mechanisms underlying Ferroptosis in HIBD remain largely unclear. In this study, we found that elevated lysyl oxidase (LOX) expression correlates closely with the severity of HIE, suggesting LOX as a potential biomarker for HIE. LOX expression levels and enzymatic activity were significantly increased in HI-induced neuronal models both in vitro and in vivo. Notably, we discovered that HI-induced brain tissue injury results in increased stiffness and observed a selective upregulation of the mechanosensitive ion channel Piezo1 in both brain tissue of HIBD and primary cortex neurons. Mechanistically, LOX increases its catalytic substrates, the Collagen I/III components, promoting extracellular matrix (ECM) remodeling and possibly mediating ECM cross-linking, which leads to increased stiffness at the site of injury and subsequent activation of the Piezo1 channel. Piezo1 senses these stiffness stimuli and then induces neuronal Ferroptosis in a GPX4-dependent manner. Pharmacological inhibition of LOX or Piezo1 ameliorated brain neuronal Ferroptosis and improved learning and memory impairments. Furthermore, we identified traumatic acid (TA) as a novel LOX inhibitor that effectively suppresses LOX enzymatic activity, mitigating neuronal Ferroptosis and promoting synaptic plasticity. In conclusion, our findings elucidate a critical role for LOX-mediated ECM mechanical stress-induced Piezo1 activation in regulating ferroptotic cell death in HIBD. This mechanistic insight provides a basis for developing targeted therapies aimed at ameliorating neurological outcomes in neonates affected by HIBD.

Keywords

Ferroptosis; HIBD; LOX; Piezo1; TA.

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