A transcriptomic analysis of the interplay of ferroptosis and immune filtration in endometriosis and identification of novel therapeutic targets

Endometriosis is an inflammatory disease, involving immune cell infiltration and production of inflammatory mediators. Ferroptosis has recently been recognized as a mode of controlled cell death and the iron overload and peroxidative environment prevailing in the ectopic endometrium facilitates the occurrence of ferroptosis. In the current investigation, gene expression data was obtained from the dataset GSE7305.The variation in infiltration of immune cells amongst the samples with endometriosis and normal tissue was analysed using the CIBERSORTx tool which revealed higher infiltration of T cells gamma delta, macrophages M2, B cells naïve, T cells CD4 memory resting cells, plasma cells, T cells CD8 and mast cells activated in the tissue samples with endometriosis. An overlap of the differentially expressed genes (DEGs) and ferroptosis related genes revealed 32 ferroptosis related DEGs (FR-DEGs). GO and KEGG pathway analysis showed the FR-DEGs to be enriched in ferroptosis. The PPI network of the FR-DEGs was constructed and TP53, HMOX1, CAV1, CDKN1A, CD44, EPAS1, SLC2A1, MAP3K5, GCLC and FANCD2 were identified as the hub genes. Pearson correlation revealed significant correlation between the hub genes and infiltrating immune cells in endometriosis, thereby suggesting existence of a regulatory crosstalk between immune responses and ferroptosis in endometriosis. Hub gene- miRNA network analysis revealed that 7 of the 10 hub genes were targets of 3 miRNAs -hsa-miR-20a-5p, hsa-miR-16–5p and hsa-miR-17–5p, thereby providing further insight into the regulatory mechanisms underlying disease progression. Predictive analysis and cross validation studies revealed TP53 and CDKN1A as common targets of hsa-miR-16–5p, hsa-miR-17–5p, and hsa-miR-20a-5p, thereby revealing their regulatory roles in ferroptosis and immune modulatory pathways relevant to endometriosis. The present study indicates an important role of both immune dysregulation and ferroptosis in the pathogenesis of endometriosis and identifies ferroptosis related hub genes and their miRNA regulators as favourable novel targets for further studies and therapeutic interventions.