Transcriptomic analysis reveals inflammatory and metabolic dysregulation in unexplained female infertility

ABSTRACT Infertility is a complex condition affecting both the male and female population. Influenced by multiple factors, it remains a constant challenge due to limited understanding of endometrial abnormalities. With this study we aim to investigate the molecular basis of infertility using transcriptomic analysis of endometrial tissue from the NCBI GEO dataset GSE92324. We performed exploratory data analysis using Principal Component Analysis (PCA) to find samples variance followed by differential gene expression (DGE) analysis using DESeq2 package where we identified 168 significant genes with adjusted p-value < 0.05 and |log2FC| > 2. Upregulated genes included GPX3, CXCL14, and PPARGC1A and downregulated genes included WNK4, GJB2 , and TRPM6 . Functional enrichment using KEGG and GO showed that differentially expressed genes (DEGs) are involved in immune-inflammatory pathways, lipid metabolism and steroid biosynthesis pathways. Through Ingenuity Pathway Analysis (IPA) we identified affected canonical pathways such as increased innate immune responses, altered lipid metabolism and inhibition of mitochondrial dysfunction. Upstream regulator analysis highlighted PTEN, PRKAA1, HDAC4, IL10RA, and RAD51, which were impacting metabolic pathways and anti-inflammatory signalling. Further, through Weighted Gene Co-expression Network Analysis (WGCNA) we found a Turquoise module that had very strong and highly significant negative correlation (cor = - 0.84, respectively and P < 0.0001) with traits of interest. This led to the discovery of C7orf50 as a novel insight involved in cholesterol metabolism linked to infertility. This integrative approach reveals crucial genes, co-expression modules, and underlying pathways involved in female infertility. GRAPHICAL ABSTRACT HIGHLIGHTS From the dataset GSE92324 total of 168 significant DEGs associated with unexplained infertility were identified using adjusted p-value < 0.05 and |log2FC| > and < 2. In comparison with the CTD list we identified five genes C1orf106, C15orf59, LINC00461, C15orf48, and C10orf99 previously unknown as having direct evidence of involvement in infertility. WGCNA analysis highlighted the turquoise module as highly associated and gave the novel gene C7orf50 associated with cholesterol metabolism. IPA revealed PTEN, PRKAA1, IL10RA, and RAD51 as potential upstream regulators and inflammatory pathways, mitochondrial dysfunction as canonical pathways. The study highlights a novel link between GI inflammation and endometrial receptivity.