Li Linbo, Liu Xinjun, Si Zizhen, Wang Xidi
Central Laboratory, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo 315010, China.
Health Science Center, Ningbo University, Ningbo 315211, China.
Biomedicines. 2025 Aug 5;13(8):1913. doi: 10.3390/biomedicines13081913.
Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation participating in various diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular redox homeostasis and a key determinant of ferroptosis resistance. Nrf2 activates the expression of downstream antioxidant genes to protect cells from oxidative stress and ferroptosis. Consequently, precise regulation of Nrf2 expression is crucial. Recent studies have revealed that complex epigenetic mechanisms involving DNA methylation, histone modifications, and non-coding RNA networks regulate Nrf2 expression. DNA methylation usually suppresses while histone acetylation promotes Nrf2 expression. The influences of histone methylation on are site- and methylation degree-dependent. m6A modification stabilizes mRNA to promote Nrf2 expression and thereby inhibit ferroptosis. This article summarizes current understanding of the epigenetic mechanisms controlling Nrf2 expression and Nrf2-mediated ferroptosis pathways and their implications in disease models. The challenges associated with the epigenetic regulation of Nrf2 and future research directions are also discussed. A comprehensive understanding of this regulatory interplay could open new avenues for intervention in ferroptosis-related diseases by fine-tuning cellular redox balance through the epigenetic modulation of Nrf2.
铁死亡是一种由铁依赖性脂质过氧化驱动的独特的程序性细胞死亡形式，参与多种疾病的发生发展。核因子红细胞2相关因子2（Nrf2）是细胞氧化还原稳态的核心调节因子，也是铁死亡抗性的关键决定因素。Nrf2激活下游抗氧化基因的表达，以保护细胞免受氧化应激和铁死亡的影响。因此，精确调控Nrf2的表达至关重要。最近的研究表明，涉及DNA甲基化、组蛋白修饰和非编码RNA网络的复杂表观遗传机制调控Nrf2的表达。DNA甲基化通常抑制Nrf2的表达，而组蛋白乙酰化则促进其表达。组蛋白甲基化对Nrf2表达的影响取决于位点和甲基化程度。m6A修饰可稳定Nrf2 mRNA以促进其表达，从而抑制铁死亡。本文总结了目前对控制Nrf2表达的表观遗传机制、Nrf2介导的铁死亡途径及其在疾病模型中的意义的理解。还讨论了Nrf2表观遗传调控相关的挑战和未来的研究方向。全面了解这种调控相互作用可能通过对Nrf2进行表观遗传调控来微调细胞氧化还原平衡，从而为干预铁死亡相关疾病开辟新途径。
