目前对金属离子代谢促进骨肉瘤进展和耐药机制的认识尚不完整。本研究旨在阐明铜凋亡相关鞘脂代谢（cuprotosis-SPGs）相关基因在调节骨肉瘤细胞免疫景观、肿瘤转移和耐药性中的关键作用和机制。本研究采用多组学方法来评估铜凋亡-SPGs 对骨肉瘤患者预后的影响。利用Lasso回归分析构建预后模型，同时利用多元回归分析识别关键核心基因并生成这些基因的风险系数，从而计算每个骨肉瘤患者的风险评分。然后根据患者的风险评分将患者分为高风险组和低风险组。使用 ESTIMATE 和 CIBERSORT 算法分析这些风险组内的免疫细胞浸润水平，以构建免疫景观。进行单细胞分析是为了更准确地描述免疫细胞亚型中铜凋亡-SPG 的表达模式。最后，在骨肉瘤细胞上进行实验，验证铜凋亡-鞘脂信号网络在调节细胞迁移和凋亡中的作用。在本研究中，鉴定了七种铜凋亡-SPG，并用于构建骨肉瘤患者的预后模型。除了预测生存率外，该模型还证明了预测化疗药物反应的可靠性。结果表明，高铜凋亡-鞘脂代谢评分与 CD8 T 细胞浸润减少密切相关，表明骨肉瘤患者预后不良。细胞功能分析显示，铜凋亡-SPGs调节LC3B/ERK信号通路，从而引发细胞死亡并损害骨肉瘤细胞的迁移能力。铜凋亡相关的鞘脂代谢对骨肉瘤细胞的存活和迁移以及CD8的影响T 细胞浸润凸显了针对骨肉瘤患者的铜离子代谢作为一种有前途的策略的潜力。版权所有 © 2024 Li、Fang、Liu、Luo 和 Wang。

The current understanding of the mechanisms by which metal ion metabolism promotes the progression and drug resistance of osteosarcoma remains incomplete. This study aims to elucidate the key roles and mechanisms of genes involved in cuproptosis-related sphingolipid metabolism (cuproptosis-SPGs) in regulating the immune landscape, tumor metastasis, and drug resistance in osteosarcoma cells.This study employed multi-omics approaches to assess the impact of cuproptosis-SPGs on the prognosis of osteosarcoma patients. Lasso regression analysis was utilized to construct a prognostic model, while multivariate regression analysis was applied to identify key core genes and generate risk coefficients for these genes, thereby calculating a risk score for each osteosarcoma patient. Patients were then stratified into high-risk and low-risk groups based on their risk scores. The ESTIMATE and CIBERSORT algorithms were used to analyze the level of immune cell infiltration within these risk groups to construct the immune landscape. Single-cell analysis was conducted to provide a more precise depiction of the expression patterns of cuproptosis-SPGs among immune cell subtypes. Finally, experiments on osteosarcoma cells were performed to validate the role of the cuproptosis-sphingolipid signaling network in regulating cell migration and apoptosis.In this study, seven cuproptosis-SPGs were identified and used to construct a prognostic model for osteosarcoma patients. In addition to predicting survival, the model also demonstrated reliability in forecasting the response to chemotherapy drugs. The results showed that a high cuproptosis-sphingolipid metabolism score was closely associated with reduced CD8 T cell infiltration and indicated poor prognosis in osteosarcoma patients. Cellular functional assays revealed that cuproptosis-SPGs regulated the LC3B/ERK signaling pathway, thereby triggering cell death and impairing migration capabilities in osteosarcoma cells.The impact of cuproptosis-related sphingolipid metabolism on the survival and migration of osteosarcoma cells, as well as on CD8 T cell infiltration, highlights the potential of targeting copper ion metabolism as a promising strategy for osteosarcoma patients.Copyright © 2024 Li, Fang, Liu, Luo and Wang.