CXCL10-based gene cluster model serves as a potential diagnostic biomarker for premature ovarian failure

Abstract

Objective Premature ovarian failure (POF) is a disease with high clinical heterogeneity. Subsequently, its diagnosis is challenging. CXCL10 which is a small signaling protein involved in immune response and inflammation may have diagnostic potential in detection of premature ovarian insufficiency. Therefore, this study aimed to investigate CXCL10 based diagnostic biomarkers for POF. Methods Transcriptome data for POF was obtained from the Gene Expression Omnibus (GEO) database (GSE39501). Principal component analysis (PCA) assessed CXCL10 expression in patients with POF. The receiver operating characteristic (ROC) curve, analyzed using PlotROC, demonstrated the diagnostic potential of CXCL10 and CXCL10-based models for POF. Differentially expressed genes (DEGs) in the control group of POF were identified using DEbylimma. PlotVenn was used to determine the overlap between the POF-control group and the high-/low-expression CXCL10 groups. QuadrantPlot was employed to detect CXCL10-dysregulated genes in POF. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were conducted on DEGs using RunMulti Group cluster Profiler. A POF model was induced with cisplatin (DDP) using KGN cells. RT-qPCR and Western blot were used to measure the expression of CXCL10, apoptosis-related proteins, and peroxisome proliferator–activated receptor (PPAR) signaling pathway-related proteins in this model, following siRNA-mediated silencing of CXCL10. Flow cytometry was employed to assess the apoptosis of KGN cells after CXCL10 downregulation. Results The expression of CXCL10 is dysregulated in POF, and it shows promising diagnostic potential for POF, as evidenced by an area under the curve value of 1. In POF, we found 3,362 up-regulated and 3,969 down-regulated DEGs compared to healthy controls, while the high- and low-expression groups of POF (comprising samples above and below the median CXCL10 expression) exhibited 1,304 up-regulated and 1,315 down-regulated DEGs. Among these, 786 DEGs consistently displayed dysregulation in POF due to CXCL10 influence. Enrichment analysis indicated that the PPAR signaling pathway was activated by CXCL10 in POF. The CXCL10-based model (including CXCL10, Itga2, and Raf1) holds potential as a diagnostic biomarker for POF. Additionally, in the DDP-induced KGN cell model, interfering with CXCL10 expression promoted the secretion of estradiol, and reduced apoptosis. Furthermore, CXCL10 silencing led to decreased expression levels of PPARβ and long-chain acyl-CoA synthetase 1 compared to the Si-NC group. These results suggest that CXCL10 influences the progression of POF through the PPAR signaling pathway. Conclusion The CXCL10-based model, demonstrating perfect diagnostic accuracy for POF and comprising CXCL10, Itga2, and Raf1, holds potential as a valuable diagnostic biomarker. Thus, the expression levels of these genes may collectively provide valuable diagnostic information for POF.