1. Academic Validation
  2. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

  • Cell Death Discov. 2022 Feb 2;8(1):43. doi: 10.1038/s41420-021-00807-3.
Ruyuan He  # 1 Bohao Liu  # 1 Rui Xiong 1 Boxin Geng 2 Heng Meng 1 Weichen Lin 1 Bo Hao 1 Lin Zhang 1 Wei Wang 1 Wenyang Jiang 1 Ning Li 3 Qing Geng 4
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
  • 2 School of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, China.
  • 3 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China. md.lining@whu.edu.cn.
  • 4 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China. gengqingwhu@whu.edu.cn.
  • # Contributed equally.
Abstract

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, Ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and Ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on Ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with Ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of Glutathione Peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of Ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that Ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting Ferroptosis.

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