AI 中文总结
综述DNA甲基化在表观遗传调控中的机制与作用，评估从传统抑制剂到前沿系统等DNA甲基化调节剂，指出其缺乏基因选择性的问题，强调需精准、位点特异性工具推动癌症研究与治疗策略发展。
AI 中文摘要
DNA甲基化可作为化疗药物利用的毒性烷基化反应诱导癌细胞死亡。然而，微调的DNA甲基化在细胞生理中起基本作用，特别是在基因表达的表观遗传调控中。其功能作用已被阐明为基因组位点特异性且与其他表观遗传因素密切相关。在DNA甲基转移酶抑制剂临床获批后，人们致力于开发调节表观遗传DNA甲基化的药物工具，但这些药物缺乏基因选择性限制了疗效并增加脱靶毒性。本文综述了DNA甲基化在表观遗传调控中的机制和作用，评估了从传统DNMT抑制剂到前沿CRISPR-dCas9融合系统等DNA甲基化调节剂的现状及临床相关性，强调了精准、位点特异性工具对癌症研究和治疗策略的必要性。
英文摘要
DNA methylation can function as a toxic alkylation reaction exploited by chemotherapeutic agents to induce cancer cell death. However, finely tuned DNA methylation plays a fundamental role in cellular physiology, particularly in the epigenetic regulation of gene expression. Once thought to act solely as a repressor of gene transcription, its functional role has since been elucidated as genomic locus-specific and deeply connected with other epigenetic factors. Following the clinical approval of DNA methyltransferase inhibitors, such as Azacitidine and Decitabine, for the treatment of haematological malignancies, considerable efforts have been devoted to developing pharmacological tools that modulate epigenetic DNA methylation. However, the lack of gene selectivity in these agents limits their therapeutic efficacy and increases off-target toxicity. Moreover, the non-gene-selective nature of current DNA methylation-targeting molecules fails to meet the standards required to discern the nuanced roles of DNA methylation across diverse pathophysiological contexts and genomic loci, particularly in an era where next-generation sequencing and omics technologies enable hi ghresolution epigenetic analyses. In this review, we examine the mechanisms and roles of DNA methylation in epigenetic regulation, evaluate the current landscape of DNA methylation modulators, from traditional DNMT inhibitors to cutting-edge CRISPR-dCas9 fusion systems and protein-protein interaction disruptors, and discuss their clinical relevance. Finally, we emphasise the need for precise, locus-specific tools to advance both cancer research and therapeutic strategies.
Journal refChemical Research in Toxicology, 2026
