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Dimethyl fumarate alleviates inflammation during high altitude hypoxia induced acute lung injury by upregulating Nrf2/SLC7A11 pathway in ferroptosis

Year: 2025

Type: article

Abstract: BACKGROUND: This study aims to investigate the impact of high altitude (HA) hypoxia on ferroptosis in lung tissue and the evaluate the preventative effect of Dimethyl fumarate (DMF) on lung inflammation. METHODS: Proteomic analysis was performed in plasma of volunteers ascending to high altitude, lung tissue of ALI rats, co-cultured lung epithelial (BEAS-2B cells) and macrophages (THP-1 cells) under hypoxia, either individually or in co-culture setting. DMF was pre-treated with rats or BEAS-2B cells before ferroptosis indexes and inflammatory cytokines were determined. Knock-down or overexpression of SLC7A11 in BEAS-2B cell was performed to further verify the role of DMF in alleviating ferroptosis and inflammation in ALI. RESULTS: Proteomic analysis of human plasma, rat lung tissue and lung epithelial cells identified Differentially expressed proteins (DEPs) enriched in the ferroptosis. HA exposure increased inflammatory response and lung injury, which could be alleviated by DMF. Co-culture of two cell types lead to a more pronounced ferroptotic response in BEAS-2B cells and an elevated level of cytokine expression in THP-1 cells under hypoxia condition, which could also be ameliorated by DMF. Knockdown of SLC7A11 results in a reversal of ferroptosis and macrophage mediated inflammation, which were improved by increasing Nrf2 expression through DMF treatment. CONCLUSION: This study revealed that a reciprocal regulatory relationship between ferroptosis of lung epithelial cells and macrophage-mediated inflammation was one of the critical mechanisms contributing to HA exposure triggered ALI. Furthermore, DMF could alleviates hypoxia induced ALI by upregulating Nrf2/SLC7A11 pathway, making it a potential protective agent against HA hypoxia induced ALI.

Source: Clinical Proteomics

DOI: 10.1186/s12014-025-09566-0