SPOP和CHD1在ACSL4调控中的差异化作用揭示了靶向铁死亡的情境依赖性脆弱性
Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.
摘要(中文译文)
遗传异质性导致了癌症治疗反应的差异。频繁发生的SPOP突变和反复出现的CHD1缺失定义了前列腺癌(PCa)不同的分子亚型,这些亚型对抗雄激素治疗的反应存在差异。铁死亡是一种由脂质过氧化驱动的铁依赖性细胞死亡机制,已成为一种有前景的抗癌策略。在本研究中,我们确定SPOP突变和CHD1缺失是前列腺癌铁死亡易感性的关键遗传决定因素。利用基因工程化的人源和小鼠模型,我们发现SPOP突变增强而CHD1缺失削弱靶向GPX4的铁死亡诱导剂的疗效。在机制上,SPOP和CHD1通过拮抗性调控MYC-ACSL4轴对铁死亡发挥相反的作用。此外,我们证明使用降胆固醇药物靶向胆固醇代谢可恢复ACSL4表达,并使SPOP/CHD1共缺失肿瘤对铁死亡诱导治疗重新敏感。我们的研究确立了SPOP/CHD1作为铁死亡的上游遗传调控因子,并提供了生物标志物驱动的联合策略,以增强晚期前列腺癌患者的铁死亡基础治疗。
Abstract
Genetic heterogeneity contributes to the variable therapeutic responses in cancers. Frequent SPOP mutations and recurrent CHD1 deletions define distinct molecular subtypes of prostate cancer (PCa) with differential responses to anti-androgen therapy. Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, has emerged as a promising anticancer strategy. Here, we identify SPOP mutations and CHD1 deletion as key genetic determinants of ferroptosis susceptibility in PCa. Using genetically engineered human and murine models, we show that SPOP mutations enhance, whereas CHD1 deletion impairs, the efficacy of ferroptosis inducers targeting GPX4. Mechanistically, SPOP and CHD1 exert opposing effects on ferroptosis by antagonistically regulating the MYC-ACSL4 axis. Furthermore, we demonstrate that targeting cholesterol metabolism with cholesterol-lowering agents restores ACSL4 expression and re-sensitizes SPOP/CHD1 co-deficient tumors to ferroptosis-inducing therapy. Our findings establish SPOP/CHD1 as upstream genetic regulators of ferroptosis and provide biomarker-driven combinatorial strategies to enhance ferroptosis-based therapy in men with advanced PCa.
如何引用
AMA
Feiyu Chen, Qidong Li, Qianlin Gu, Javier Leo, Xin Liang, Naayaa Mehta, et al. Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.. Nature communications. 2026; doi:10.1038/s41467-026-75010-y.
APA
Feiyu Chen, Qidong Li, Qianlin Gu, Javier Leo, Xin Liang, Naayaa Mehta, et al (2026). Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.. Nature communications. https://doi.org/10.1038/s41467-026-75010-y
GB/T 7714
Feiyu Chen, Qidong Li, Qianlin Gu, Javier Leo, Xin Liang, Naayaa Mehta, et al. Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75010-y.
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