GPX3 downregulation in alveolar macrophages amplifies IL-17-dependent redox-inflammation crosstalk in ARDS

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which bidirectional amplification between oxidative stress and inflammation critically drives disease progression. However, the cellular hubs mediating this crosstalk and offering therapeutic leverage remain unclear.

This study aims to reveal the key cellular and molecular mechanisms linking oxidative stress and inflammation in ARDS, and to prioritize candidate small-molecule therapeutics targeting this linkage.

We performed single-cell RNA sequencing (scRNA-seq) on lung tissues from ARDS patients and matched controls to identify key cellular hubs, validated major findings in inflammatory models, and applied a network pharmacology framework to prioritize candidate therapeutic compounds.

scRNA-seq analysis revealed alveolar macrophages as the central cell type connecting redox and inflammatory signaling. Gene-set enrichment analysis further indicated a significant functional association between glutathione peroxidase 3 (GPX3) and the interleukin-17 (IL-17) pathway in macrophages. In both LPS-treated RAW 264.7 cells and an LPS-induced mouse ARDS model, consistent downregulation of GPX3 expression and upregulation of IL-17 signaling were observed. Mechanistically, GPX3 downregulation activated IL-17 signaling and increased oxidative stress and inflammatory cytokine release, whereas IL-17 inhibition alleviated the oxidative and inflammatory responses driven by GPX3 loss. Network pharmacology further prioritized quercetin and luteolin as candidate modulators of the GPX3-IL-17 network.

These findings identify a macrophage-centered GPX3-IL-17 hub that links oxidative stress with inflammatory amplification in ARDS and suggest potential therapeutic strategies.