Unveiling Circular RNA-Mediated Regulatory Mechanisms in Necroptosis in Premature Ovarian Failure

Necroptosis is a programmed necrotic cell death, in which dying cells rupture and release intracellular components that trigger a proinflammatory response. The current study aimed at probing the circular RNA (circRNA)-mediated regulatory mechanisms in necroptosis in premature ovarian failure (POF).

CircRNA sequencing analysis was conducted in ovarian tissues of control and POF rats and transcriptome microarrays were acquired from the GSE33423 dataset. Differential expression analysis of circRNAs and mRNAs was executed between the POF and control data. Both a necroptosis-based circRNA-microRNA (miRNA)-mRNA network and a protein-protein interaction (PPI) network were established. Then, the functional annotation and immunological traits were analyzed.

Totally, 1266 upregulated and 1283 downregulated circRNAs as well as 1101 upregulated and 1168 downregulated mRNAs were determined in the POF rats versus the controls. The differentially expressed mRNAs predominantly correlated with necroptosis. The circRNA-miRNA-mRNA networks of downregulated necroptosis genes (comprising rno_circRNA_004995-rno-miR-148b-5p-H2afy2, rno_circRNA_016998-rno-miR-29a-5p-Hmgb1, and rno_circRNA_017593-rno-miR-29a-5p-Hmgb1) and upregulated necroptosis genes (comprising rno_circRNA_015900-rno-miR-935-Stat1, rno_circRNA_007946-rno-miR-328a-3p-Stat5a, rno_circRNA_007947-rno-miR-328a-3p-Stat5a, rno_circRNA_005064-rno-miR-18a-5p-Stat1, rno_circRNA_005064-rno-miR-18a-5p-Stat5a, rno_circRNA_005115-rno-miR-22-3p-Stat1, rno_circRNA_009028-rno-miR-342-5p-Stat1, rno_circRNA_011240-rno-miR-1224-Stat5a, rno_circRNA_016078-rno-miR-711-Stat5a) were built. POF-specific necroptosis genes (STAT1, STAT5A, PLA2G4A, HMG1L1, HMGB1, AGER, EGFR, HDAC7, IFNA1, IL10RB, IL27RA, PYGL, SOCS1, TRADD, CXCL10, DDX5, EZH2, FADS2, FER, H2AFY2, HIST1H2AF, IFI44L, IL27, IRGM, MX1, NFKB2, PAFAH2, PEMT, PGM2L1, PGR, PHKA2, and PLB1) were selected since they displayed notable associations with most immune cells, immune checkpoints, chemokines, human leukocyte antigen (HLA) molecules, and immune receptors.

Altogether, we proposed the presence of widespread regulatory mechanisms of circRNAs in necroptosis and demonstrated that altered circRNA biogenesis might contribute to POF by affecting necroptosis.