Du Linna, Zhang Yueyue, Luo Jianchang, He Caidi, Lang Jiawang, Cao Xuan
Department of Rehabilitation Medicine, Taizhou Municipal Hospital (Taizhou University Affiliated Municipal Hospital), Taizhou University, Taizhou, 318000, Zhejiang, China.
Department of Basic Medicine and Medical Laboratory Science, School of Medicine, Taizhou University, Taizhou, 318000, Zhejiang, China.
Exp Hematol Oncol. 2026 Jan 26;15(1):11. doi: 10.1186/s40164-025-00737-1.
Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. The tumor immune microenvironment (TIME) significantly influences ferroptosis sensitivity in both cancer and immune cells. Recent years have witnessed major advances in understanding how multi-level regulatory mechanisms control ferroptosis in tumors, encompassing epigenetic modifications and post-translational protein regulation. Epigenetic mechanisms include DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, while post-translational modifications (PTMs) involve phosphorylation, glycosylation, ubiquitination, acetylation, methylation, and lactylation of key ferroptosis proteins. This review examines the intricate relationship between the TIME, ferroptosis, and these dual regulatory networks. We focus particularly on how epigenetic processes and PTMs synergistically control ferroptosis mediators in the TIME, exploring how ubiquitination controls protein stability, and how metabolic modifications like lactylation link cellular metabolism to ferroptosis regulation. These multilevel interactions create a complex regulatory landscape that influences cancer progression, immune evasion, and therapeutic resistance. The crosstalk between epigenetic and post-translational regulation determines ferroptosis susceptibility across different cellular contexts within tumors, with distinct modification patterns observed in cancer cells versus immune infiltrates. Additionally, we discuss emerging therapeutic strategies that simultaneously target both epigenetic and post-translational regulation of ferroptosis, including combination approaches that modulate specific modification enzymes to enhance ferroptosis induction. Understanding these complex multilevel regulatory relationships provides valuable insights for developing novel precision cancer treatment approaches that leverage the therapeutic potential of ferroptosis modulation with potentially significant clinical impact.
铁死亡是一种非凋亡性细胞死亡机制，其特征是铁依赖性膜脂质过氧化。肿瘤免疫微环境（TIME）显著影响癌症细胞和免疫细胞中铁死亡的敏感性。近年来，在理解多层次调控机制如何控制肿瘤中的铁死亡方面取得了重大进展，这些机制包括表观遗传修饰和翻译后蛋白质调控。表观遗传机制包括DNA甲基化、组蛋白修饰、非编码RNA和染色质重塑，而翻译后修饰（PTM）涉及关键铁死亡蛋白的磷酸化、糖基化、泛素化、乙酰化、甲基化和乳酰化。本综述探讨了TIME、铁死亡和这些双重调控网络之间的复杂关系。我们特别关注表观遗传过程和PTM如何协同控制TIME中的铁死亡介质，探索泛素化如何控制蛋白质稳定性，以及乳酰化等代谢修饰如何将细胞代谢与铁死亡调控联系起来。这些多层次的相互作用创造了一个复杂的调控格局，影响癌症进展、免疫逃逸和治疗抗性。表观遗传调控和翻译后调控之间的相互作用决定了肿瘤内不同细胞环境中铁死亡的易感性，在癌细胞与免疫浸润细胞中观察到不同的修饰模式。此外，我们讨论了同时靶向铁死亡的表观遗传调控和翻译后调控的新兴治疗策略，包括调节特定修饰酶以增强铁死亡诱导的联合方法。理解这些复杂的多层次调控关系为开发新的精准癌症治疗方法提供了有价值的见解，这些方法利用铁死亡调节的治疗潜力，可能具有重大的临床影响。
