Identifying potential ferroptosis key genes for diagnosis and treatment of postmenopausal osteoporosis through competitive endogenous RNA network analysis.

OBJECTIVE: Postmenopausal osteoporosis (PMOP) is a common systemic metabolic bone disorder that is owing to the reduced estrogen secretion and imbalance of bone absorption and bone formation in postmenopausal women. Ferroptosis has been identified as a novel modulatory mechanism of osteoporosis. Nevertheless, the particular modulatory mechanism between ferroptosis and PMOP is still unclear. The objective of the current investigation was to detect potential biomarkers connected to ferroptosis in PMOP and discover its probable mechanism through bioinformatics.

METHODS: We downloaded PMOP-related microarray datasets from the database of Gene Expression Omnibus (GEO) and obtained the differentially expressed genes (DEGs). Utilizing bioinformatics analysis, the DEGs were intersected with the ferroptosis dataset to obtain ferroptosis-connected mRNAs. Enrichment analysis employing KOBAS 3.0 was conducted to comprehend the biological functions and enrichment pathways of the DEGs. The generation of the protein-protein interaction (PPI) network was conducted with the aim of identifying central genes. Lastly, the coexpression and competitive endogenous RNA (ceRNA) networks were built using Cytoscape. With the help of external datasets GSE56815 to verify the reliability of the hub genes by plotting ROC curves.

RESULTS: We identified 178 DE microRNAs (miRNAs), 138 DE circular RNAs (circRNAs), and 86 ferroptosis-related mRNAs. Enrichment analysis exhibited that mRNAs were primarily connected with the signaling pathways of PI3K/Akt, metabolism, mTOR, FoxO, HIF-1, AMPK, MAPK, ferroptosis, VEGF, and NOD-like receptors. Generation of the PPI network detected eight hub genes. The circRNA/miR-23b-3p/PTEN axis may relieve PMOP by inhibiting ferroptosis through targeting the pathway of PI3K/Akt signaling, which is a vital modulatory pathway for PMOP progression. Moreover, the ROC curves ultimately indicates that the four hub genes have greater diagnostic importance in PMOP samples in contrast to the normal group samples, which may be possible markers for PMOP diagnosis.

CONCLUSIONS: Bioinformatics analysis identified four hub genes, namely, PTEN, SIRT1, VEGFA, and KRAS, as potential biomarkers for PMOP diagnosis and management. Moreover, the circRNA/miR-23b-3p/PTEN axis may relieve PMOP by suppressing ferroptosis through targeting the pathway of PI3K/Akt signaling, providing a new avenue to explore the pathogenesis of PMOP.