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

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.

Research Progress on the Mechanism of Itaconate Regulating Macrophage Immunometabolism

“…4-OI can significantly increase GCLM levels and reverse LPS-induced decrease in GCLM levels. Previous studies have confirmed that it can be controlled by Nrf2 ( 52 ).…”

“…The new study has found that there are significant differences in ferroptosis-related genes in sepsis-induced ALI mice pretreated with itaconate derivatives ( 52 ). Markers of ferroptosis are cystine/glutamate transporter (SLC7A11), GPX4, and prostaglandin-in-peroxide synthase 2 (PTGS2) ( 53 ).…”

“…Markers of ferroptosis are cystine/glutamate transporter (SLC7A11), GPX4, and prostaglandin-in-peroxide synthase 2 (PTGS2) ( 53 ). After 4-OI administration, the marker of ferroptosis, GPX4 increased significantly, while PTGS2 decreased ( 52 ). The presence of gene and protein changes associated with ferroptosis in experimental mice suggests itaconate may influence this process.…”

“…To further corroborate the above findings, the relevant trials were conducted again in Nrf2-KO mice to construct ALI models, the loss of Nrf2 aggravated the sepsis-induced ALI, and the protective effect of 4-OI on Nrf2-deficient ALI mice disappeared. The researchers found that 4-OI protects LPS mice by modulating Nrf2 against ferroptosis, while also reducing LPS-induced tissue iron levels in Nrf2-deficient mice, revealing that 4-OI can also regulate cytoplasmic iron through Nrf2’s non-dependent mechanism ( 52 ). Despite the above findings, it can still be concluded that itaconate inhibits ferroptosis in monocyte macrophages by activating Nrf2 and increasing Nrf2 levels, and has a protective effect on ALI where sepsis occurs.…”

Ferroptosis in Cardiovascular Diseases: Current Status, Challenges, and Future Perspectives

“…Treating macrophage with LPS to generate sepsis models in vitro, it is shown that both 4-octyl itaconate (4-OI) and ferrostatin-1 significantly upregulate the expression of GPX4, SLC7A11C, and Nrf2, exhibiting a protective effect for THP-1 macrophage and inhibiting lipid peroxidation induced by LPS. Further, this ferroptosis resistance is highly dependent on Nrf2 [60].…”