■骨关节炎(OA)中软骨细胞铁性凋亡的机制尚未完全阐明。本研究旨在鉴定参与软骨细胞铁性凋亡的关键铁性凋亡相关基因(FRGs)。
■LASSO,SVM-RFE,并进行受试者工作特征曲线(ROC)筛选关键差异表达的FRG(DEFRG)。使用GO进行功能分析,和KEGG分析。无监督聚类分析用于识别铁死亡相关模式。构建CeRNA网络来预测上游miRNA和lncRNA。最后,我们通过体内和体外实验验证了EGFR在软骨细胞铁性凋亡中的作用.
■在OA和正常软骨之间总共鉴定出42个DEFRG。GO和KEGG分析表明,这些DEFRGs显著参与铁死亡相关的生物学过程和途径,如细胞对氧化应激的反应,细胞程序性死亡的正向调节,MAPK和PI3K-Akt信号通路。此外,四个关键DEFRG,包括ACSF2,AURKA,EGFR,和KLHL24被认为是OA的潜在生物标志物。此外,确定了两种不同的铁死亡相关模式,共鉴定出882个差异表达基因,这些基因可能参与细胞外基质降解和炎症反应。此外,CeRNA网络显示EGFR可以被3个lncRNAs和4个miRNAs竞争性调控。重要的是,EGFR在人OA软骨中表达下调,OA小鼠模型,和erastin诱导软骨细胞。EGFR抑制可以诱导软骨细胞铁性凋亡和ECM降解的发生,这可以通过添加Ferrostatin-1来逆转。
■我们的研究确定了ACSF2,AURKA,EGFR,和KLHL24作为OA中铁凋亡相关的生物标志物。此外,我们对EGFR在调节软骨细胞铁性凋亡中的作用进行了初步研究。这些发现为OA的分子机制提供了新的见解。
UNASSIGNED: The mechanisms of chondrocytes ferroptosis in osteoarthritis (OA) have not yet been fully elucidated. This
study aimed to identify key ferroptosis related genes (FRGs) involved in chondrocytes ferroptosis.
UNASSIGNED: LASSO, SVM-RFE, and receiver operating characteristic curve (ROC) were performed to screen key differentially expressed FRGs (DEFRGs). Functional analyses were conducted using GO, and KEGG analyses. Unsupervised clustering analysis was used to identify ferroptosis related patterns. The CeRNA network was constructed to predict the upstream miRNAs and lncRNAs. Finally, we validated the role of EGFR in chondrocytes ferroptosis using in vivo and in vitro experiments.
UNASSIGNED: A total of 42 DEFRGs were identified between OA and normal cartilages. GO and KEGG analyses indicated that these DEFRGs were significantly engaged in ferroptosis related biological processes and pathways, such as cellular response to oxidative stress, positive regulation of programmed cell death, MAPK and PI3K-Akt signaling pathways. Moreover, four key DEFRGs, including ACSF2, AURKA, EGFR, and KLHL24, were considered as potential biomarkers of OA. Moreover, two distinct ferroptosis related patterns were determined, and a total of 882 differentially expressed genes were identified which might participate in extracellular matrix degradation and inflammatory response. In addition, the CeRNA network showed that EGFR could be competitively regulated by 3 lncRNAs and 4 miRNAs. Significantly, the expression of EGFR was downregulated in human OA cartilages, OA mouse model, and erastin induced chondrocytes. EGFR inhibition could induce the occurrence of chondrocytes ferroptosis and ECM degradation which could be reversed by the addition of Ferrostatin-1.
UNASSIGNED: Our
study has identified ACSF2, AURKA, EGFR, and KLHL24 as ferroptosis-related biomarkers in OA. Furthermore, we have conducted a preliminary investigation into the role of EGFR in regulating chondrocytes ferroptosis. These findings offer novel insights into the molecular mechanisms underlying OA.