ArticleAmerican journal of respiratory cell and molecular biology2024
Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.
Article in American journal of respiratory cell and molecular biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 5 citations in OpenAlex.
- Article
- Bile acid signaling at the gut-vascular interface: a novel modulator of hantavirus endothelial barrier dysfunction.Frontiers in cellular and infection microbiology · 2026Article
- Ferroptosis in smoke inhalation injury: from mechanisms to potential therapeutic targets.Frontiers in cell and developmental biology · 2026Review
- From "metabolic storm" to "immune paralysis": the dynamic evolution of macrophages and metabolism reprogramming in ARDS.Frontiers in immunology · 2025Review
- Farnesoid X receptor (FXR) as a potential therapeutic target for lung diseases: a narrative review.Journal of thoracic disease · 2024Review
- Pumping Iron Burns Fat in Lung Injury.American journal of respiratory cell and molecular biology · 2024Article
- Discovery and Validation of Ferroptosis-Associated Genes of Ulcerative Colitis.Journal of inflammation research · 2024Article
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22 authors at 3 institutions in 1 country.
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Abstract
Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.
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