Li Houxi, Deng Tian, Yan Mingyue, Wang Ronghuan, Ma Xiao, Zong Xiangyu, Wang Tianrui, Li Feng, Wu Xiaolin
Department of Orthopedics, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
Department of Neurology, Weifang People's Hospital, Weifang, 261041, China.
Curr Med Chem. 2025 Jul 7. doi: 10.2174/0109298673359541250527042918.
Osteosarcoma (OS) is one of the most common primary malignancies in children and adolescents. Disulfidptosis, a newly identified form of metabolically induced programmed cell death triggered by disulfide stress, has not yet been explored in OS.
We integrated data from public databases and applied a series of bioinformatics approaches, including clustering analysis to classify OS subtypes, and Cox and LASSO regression analysis to identify prognostic disulfidptosis-related genes (DRGs). Enrichment analysis was performed to explore the biological pathways associated with DRG-related molecular subtypes. The immune infiltration landscape was assessed to understand the tumor microenvironment in different risk subgroups. Additionally, drug sensitivity analysis was conducted to evaluate the potential clinical therapeutic strategies of the identified DRG score subgroups. The distribution of DRG expression across OS cell subtypes was further analyzed using single-cell RNA sequencing. In vitro assays, including Western blotting, qRT-PCR, and cell migration and invasion assays, were conducted to validate POLR1D expression and function in OS cells.
We established a DRG-based prognostic model that effectively stratifies OS patients into distinct risk groups with different survival outcomes. The model also revealed significant differences in immune cell infiltration between high and low DRG scores group, suggesting a link between disulfidptosis and the OS immune microenvironment. Drug sensitivity analysis indicated that the DRG signature could guide personalized therapeutic strategies. Single-cell RNA sequencing revealed heterogeneous expression of DRG signature across OS cell subtypes. Functional assays confirmed that POLR1D was aberrantly overexpressed in OS cells and promotes their migration and invasion, supporting its role as a potential oncogenic driver in OS.
Our study is the first to investigate the role of DRGs for risk stratification in OS, providing new insights and targets into OS pathogenesis.
骨肉瘤（OS）是儿童和青少年中最常见的原发性恶性肿瘤之一。二硫键介导的细胞焦亡是一种新发现的由二硫键应激引发的代谢诱导程序性细胞死亡形式，尚未在骨肉瘤中进行研究。
我们整合了来自公共数据库的数据，并应用了一系列生物信息学方法，包括聚类分析以对骨肉瘤亚型进行分类，以及Cox和LASSO回归分析以鉴定与二硫键介导的细胞焦亡相关的预后基因（DRGs）。进行富集分析以探索与DRG相关分子亚型相关的生物学途径。评估免疫浸润情况以了解不同风险亚组中的肿瘤微环境。此外，进行药物敏感性分析以评估所鉴定的DRG评分亚组的潜在临床治疗策略。使用单细胞RNA测序进一步分析DRG表达在骨肉瘤细胞亚型中的分布。进行了包括蛋白质免疫印迹、qRT-PCR以及细胞迁移和侵袭试验在内的体外试验，以验证POLR1D在骨肉瘤细胞中的表达和功能。
我们建立了一个基于DRG的预后模型，该模型有效地将骨肉瘤患者分层为具有不同生存结果的不同风险组。该模型还揭示了高DRG评分组和低DRG评分组之间免疫细胞浸润的显著差异，表明二硫键介导的细胞焦亡与骨肉瘤免疫微环境之间存在联系。药物敏感性分析表明，DRG特征可以指导个性化治疗策略。单细胞RNA测序揭示了DRG特征在骨肉瘤细胞亚型中的异质表达。功能试验证实，POLR1D在骨肉瘤细胞中异常过表达，并促进其迁移和侵袭，支持其作为骨肉瘤中潜在致癌驱动因子的作用。
我们的研究首次探讨了DRGs在骨肉瘤风险分层中的作用，为骨肉瘤发病机制提供了新的见解和靶点。
