Farnesoid X Receptor Protects Murine Lung Against IL-6-promoted Ferroptosis Induced by Poly(I:C).

Various infections trigger a storm of pro-inflammatory 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 model of the RNA virus-infected lung injury. In this study, a intratracheal instillation of poly(I:C) with or without IL-6 neutralizing antibody model combined with metabonomics, transcriptomics and so on to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased IL-6 level, and the up-regulated IL-6 further induced lung ferroptosis, especially in AT2 cells. Meanwhile, the lung regeneration was impaired. Mechanistically, metabolomics 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 ferroptosis microenvironment, IL-6 receptor monoclonal antibody, tocilizumab increased FXR expression, and subsequently increased Yes-associated protein (YAP) level by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, present study provides the evidence that IL-6 promotes ferroptosis and impairs regeneration of AT2 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.