The Role of IL-33 and RUNX2 in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Background: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by abnormal fibrosis of the lung tissue, leading to a gradual decline in lung function. The exact cause of this disease is not well understood, hence the term "idiopathic." Although the incidence of IPF is not high, it significantly impacts the quality of life and life expectancy of patients. The molecular mechanisms underlying IPF, including immune responses and fibroblast activation, remain insufficiently understood. This study explores the roles of interleukin-33 (IL-33) and RUNX2 in the pathogenesis of pulmonary fibrosis, aiming to identify novel therapeutic targets. Methods: A comprehensive approach combining bioinformatics analysis, molecular docking, single-cell RNA sequencing, and both in vitro and in vivo experimental models was used to investigate the interaction between IL-33 and RUNX2 in IPF. Gene expression analysis, KEGG pathway enrichment, and co-immunoprecipitation assays were performed to validate. In vitro inflammation and apoptosis assays were conducted using BEAS-2B lung epithelial cells, and in vivo fibrosis models were established in mice. Results: Bioinformatics analysis revealed the upregulation of IL-33 and RUNX2 in pulmonary fibrosis, with a significant correlation between these two molecules. In vitro, RUNX2 overexpression exacerbated BLM-induced inflammation and apoptosis, while knockdown of RUNX2 attenuated these effects. Co-immunoprecipitation confirmed the physical interaction between IL-33 and RUNX2. In vivo, IL-33 knockout mice exhibited exacerbated fibrosis, highlighting a complex dual role of IL-33 in the disease process. Conclusions: This study identifies the RUNX2-IL-33 axis as a key mediator in pulmonary fibrosis. Our findings provide new insights into the molecular mechanisms of IPF and suggest that targeting the RUNX2-IL-33 interaction could represent a promising therapeutic strategy for fibrosis-related diseases.