Ali Awais, Ali Syed Luqman, Ullah Waseef, Khan Asifullah
Department of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan, Pakistan.
Cell Biochem Biophys. 2025 Apr 17. doi: 10.1007/s12013-025-01743-0.
Multiple myeloma (MM) is a highly malignant hematological tumor with a low overall survival rate, making the identification of innovative prognostic markers essential due to its complex and heterogeneous nature. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, is now recognized as crucial in tumor development and progression. Consequently, ferroptosis-related genes (FRGs) are emerging as promising therapeutic targets and prognostic indicators. However, the specific roles and predictive value of FRGs in MM still remain unclear. The current study was therefore conceived to examine the possible involvement of FRGs in MM. FRGs data was obtained from the FerrDb resource. The datasets GSE133346 and GSE166122, sourced from the Gene Expression Omnibus (GEO), provided gene expression data for both healthy and MM individuals. The differentially expressed-FRGs (DE-FRGs) were identified using the limma and DESeq2 packages in R. Functional pathways were analyzed through Gene Ontology (GO) and KEGG enrichment analyses. The miRWalk database was used for miRNA association and enrichment analysis with hub genes. Prognosis-related genes were evaluated using Kaplan-Meier survival analyses. We identified 1400 differentially expressed genes and cross-referenced them with FRGs, ultimately selecting 17 as DE-FRGs or hub genes. GO analysis revealed that the primary enriched functions of these hub genes are sister chromatid segregation, condensed chromosome centromeric region, C-C chemokine receptor activity, and C-C chemokine binding. KEGG pathway analysis showed that these overlapped genes were enriched in several pathways, including cell cycle, viral protein interaction with cytokine and cytokine receptor, as well as breast and prostate cancers involved pathways. Furthermore, significant enrichment was observed in glycolysis, gluconeogenesis, and the citrate cycle pathways based on miRNAs association with the candidate genes. The CAV1, CD44, TFRC, DPP4, and GJA1 are identified as top five significant hub DE-FRGs based on protein-protein interaction (PPI) analysis from multiple resources. Survival analysis eventually identified CAV1, CD44, and TFRC as the top-ranked DE-FRGs associated with overall survival, underscoring their crucial role in MM. This study identifies CAV1, CD44, and TFRC as key FRGs associated with the prognosis of MM, suggesting their potential as valuable prognostic markers and therapeutic targets to improve patient outcomes.
多发性骨髓瘤（MM）是一种高度恶性的血液肿瘤，总体生存率较低，由于其性质复杂且具有异质性，因此识别创新的预后标志物至关重要。铁死亡是一种由脂质过氧化驱动的铁依赖性细胞死亡形式，现在被认为在肿瘤的发生和发展中起着关键作用。因此，铁死亡相关基因（FRGs）正成为有前景的治疗靶点和预后指标。然而，FRGs在MM中的具体作用和预测价值仍不清楚。因此，本研究旨在探讨FRGs在MM中可能的作用。FRGs数据来自FerrDb资源。来自基因表达综合数据库（GEO）的数据集GSE133346和GSE166122提供了健康人和MM患者的基因表达数据。使用R语言中的limma和DESeq2软件包鉴定差异表达的FRGs（DE-FRGs）。通过基因本体论（GO）和KEGG富集分析对功能途径进行分析。miRWalk数据库用于miRNA与枢纽基因的关联和富集分析。使用Kaplan-Meier生存分析评估预后相关基因。我们鉴定出1400个差异表达基因，并将它们与FRGs进行交叉比对，最终选择了17个作为DE-FRGs或枢纽基因。GO分析显示，这些枢纽基因的主要富集功能是姐妹染色单体分离、浓缩染色体着丝粒区域、C-C趋化因子受体活性和C-C趋化因子结合。KEGG通路分析表明，这些重叠基因在多个通路中富集，包括细胞周期、病毒蛋白与细胞因子及细胞因子受体的相互作用，以及涉及乳腺癌和前列腺癌的通路。此外，基于miRNA与候选基因的关联，在糖酵解、糖异生和柠檬酸循环通路中观察到显著富集。基于多种资源的蛋白质-蛋白质相互作用（PPI）分析，CAV1、CD44、TFRC、DPP4和GJA1被确定为前五个重要的枢纽DE-FRGs。生存分析最终确定CAV1、CD44和TFRC是与总生存相关的排名靠前的DE-FRGs，突出了它们在MM中的关键作用。本研究确定CAV1、CD44和TFRC是与MM预后相关的关键FRGs，表明它们作为有价值的预后标志物和治疗靶点以改善患者预后的潜力。
