Analysis of necroptosis-related prognostic genes and immune infiltration in idiopathic pulmonary fibrosis

Abstract

BackgroundIPF is an undetermined, progressive lung disease. Necroptosis is a type of programmed apoptosis, which involved in the pathogenesis of lung diseases like COPD and ARDS. However, necroptosis in IPF have not been adequately studied. This study aimed to investigate the necroptosis in IPF and the relationship between necroptosis and immune infiltration, to construct a prognostic prediction model of IPF based on necroptosis-related genes.MethodsGSE110147 was downloaded from the GEO database and utilized to analyze the expression of necroptosis-related differentially expressed genes (NRDEGs). Then NRDEGs were used to construct protein-protein interaction (PPI) networks in the STRING database, and Cytoscape software was used to identify and visualize hub genes. Necroptosis-related prognosticgenes were explored in GSE70866, and a prognostic prediction model was constructed. The ImmuCellAI algorithm was utilized to analyze the landscape of immune infiltration in GSE110147. The single-cell RNA sequencing dataset GSE122960 was used to explore the association between necroptosis and type II alveolar epithelial cells (AT II) in IPF. The GSE213001 and GSE93606 were used for external validation. The expression of prognostic genes was quantified using RT-qPCRin the IPF A549 cell model, and was further verified by western blotting in the bleomycin-induced pulmonary fibrosis mouse model.ResultsIt was observed that necroptosis-related signaling pathways were abundantly enriched in IPF. 29 NRDEGs were screened, of which 12 showed consistent expression trends in GSE213001. Spearman correlation analysis showed that the expression of NRDEGs was positively correlated with the infiltration of proinflammatory immune cells, and negatively correlated with the infiltration of anti-inflammatory immune cells. NRDEGs, including MLKL, were highly expressed in AT II of fibrotic lung tissue. A necroptosis-related prediction model was constructed based on 4 NRDEGsby the cox stepwise regression. In the validation dataset GSE93606, the prognostic prediction model showed good applicability. The verification results of RT-qPCR and western blotting showed the reliability of most of the conclusions.ConclusionsThis study revealed that necroptosis existed in IPF and might occur in AT II. Necroptosis was associated with immune infiltration, suggesting that necroptosis of AT II might involve in IPF by activating immune infiltration and immune response.

Identification of necroptosis-related features in diabetic nephropathy and analysis of their immune microenvironent and inflammatory response

“…Subsequently, via the selection of ML and WGCNA, a total of 8 significant NRDEGs were identified, including CFLAR, FMR1, GSDMD, IKBKB, MAP3K7, NFKBIA, PTGES3, and SFTPA1. Particularly, several significant NRDEGs have been confirmed that regulated the immune landscape and inflammatory response via necroptosis (Yu et al, 2022;Chen et al, 2023). CFLAR is a crucial regulator in apoptosis, autophagy, and necroptosis [23,392,074].…”

Roles of telocytes dominated cell–cell communication in fibroproliferative acute respiratory distress syndrome

“…Multiple aberrant pathways interconnect to result in pulmonary fibrosis in a subset of individuals who develop ARDS 44 . Important mediators include the dysregulated release of matrix metalloproteinases during the inflammatory phase of ARDS, which causes epithelial and endothelial injury and unchecked fibroproliferation 45 (Figure 4 A,B).…”

Cell type‐specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases

“…Apart from apoptosis, necroptosis occurs primarily in alveolar epithelial cells during IPF. 98 RIPK3-based necroptosis in alveolar epithelial cells is involved in IPF via releasing DAMPs. 97 Mechanically, homozygous missense mutations in SFTPA1 trigger Type II alveolar epithelial cell necroptosis during IPF via JNK-based upregulation of RIPK3.…”