Necroptosis in recurrent implantation failure: A bioinformatics analysis of key genes and therapeutic targets

Recurrent implantation failure (RIF) is a significant challenge in assisted reproductive technology (ART), potentially influenced by necroptosis, a form of cell death associated with various diseases. This study aimed to explore the role of necroptosis in RIF. By analyzing RNA-sequencing data from the Gene Expression Omnibus database, we identified differentially expressed necroptosis-related genes (DENRGs) in RIF patients compared to controls. Key genes were identified through functional enrichment, protein-protein interaction (PPI) networks, and transcription factor (TF) regulatory network analyses. Immune cell infiltration was assessed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Additionally, potential therapeutic drugs targeting these key genes were investigated using the Drug Gene Interaction Database. A total of 20 DENRGs associated with RIF were identified, with a focus on six key genes (MLKL, FASLG, XIAP, CASP1, BIRC3, and TLR3) involved in necroptosis and immune processes. These genes were used to develop a predictive model for RIF, which was validated in two datasets. The model, along with TF network analysis, highlighted the critical role of TLR3. Immune infiltration analysis revealed a reduction in 16 immune cell types in RIF patients, indicating immune system disruptions. Several drugs targeting CASP1, including nivocasan and emricasan, were identified as potential treatments. This study highlights the involvement of necroptosis in RIF, identifying key genes and immune alterations that could serve as biomarkers and therapeutic targets, paving the way for future experimental research and clinical applications.