Zhu Yifei, Huang Huixia, Chen Jiayu, Chen Keji, Yao Yanxi, Wang Yaxian, Li Yuxue, Qiu Zhibing, Li Dawei, Wei Ping
Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Biol Direct. 2025 Jul 21;20(1):88. doi: 10.1186/s13062-025-00676-1.
Ferroptosis and disulfidptosis are newly discovered forms of regulated cell death that play critical roles in cancer progression, metabolism, and immune evasion. However, their interplay and combined influence on colorectal cancer (CRC) progression remain insufficiently understood.
We developed a ferroptosis-disulfidptosis-related gene (FDRG) score using machine-learning algorithms to analyze gene modifications associated with these pathways in CRC, utilizing data from the TCGA and GEO databases. The model was externally validated, and associations with clinical outcomes, immune infiltration, mutational landscapes, immunotherapy responses, and drug sensitivity were explored. Key genes were further investigated through bioinformatics and in vitro experiments.
We constructed an 8-gene risk model with strong prognostic value, stratifying CRC patients into high- and low-risk groups with significant differences in clinical characteristics, immune cell infiltration, and therapeutic responses. Among these genes, CHMP6 was identified as a previously uncharacterized tumor suppressor in CRC. Beyond its inhibitory effect on tumor cell proliferation, migration, and invasion, CHMP6 was found to play a critical role in modulating anti-tumor immunity. Our findings established CHMP6 as a dual-function tumor suppressor that not only restrains tumor progression but also enhances immune-mediated tumor control.
The FDRG score is a robust tool for predicting CRC prognosis, tumor microenvironment dynamics, and response to immunotherapy. CHMP6 emerged as a promising tumor suppressor and potential therapeutic target, offering new insights into CRC treatment strategies.
铁死亡和二硫化物诱导的细胞死亡是新发现的程序性细胞死亡形式，在癌症进展、代谢和免疫逃逸中起关键作用。然而，它们在结直肠癌（CRC）进展中的相互作用和综合影响仍未得到充分了解。
我们使用机器学习算法开发了一种铁死亡-二硫化物诱导的细胞死亡相关基因（FDRG）评分，以分析CRC中与这些途径相关的基因修饰，利用来自TCGA和GEO数据库的数据。对该模型进行了外部验证，并探讨了其与临床结果、免疫浸润、突变图谱、免疫治疗反应和药物敏感性的关联。通过生物信息学和体外实验进一步研究关键基因。
我们构建了一个具有强大预后价值的8基因风险模型，将CRC患者分为高风险和低风险组，两组在临床特征、免疫细胞浸润和治疗反应方面存在显著差异。在这些基因中，CHMP6被鉴定为CRC中一种以前未被表征的肿瘤抑制因子。除了对肿瘤细胞增殖、迁移和侵袭的抑制作用外，CHMP6还被发现在调节抗肿瘤免疫中起关键作用。我们的研究结果确立了CHMP6作为一种双功能肿瘤抑制因子，它不仅抑制肿瘤进展，还增强免疫介导的肿瘤控制。
FDRG评分是预测CRC预后、肿瘤微环境动态和免疫治疗反应的有力工具。CHMP6成为一种有前景的肿瘤抑制因子和潜在的治疗靶点，为CRC治疗策略提供了新的见解。
