Liu Lili, Ni Saisai, Zhang Lianna, Chen Yingying, Xie Mengqi, Huang Xiaojing
Department of Emergency Medicine, Ningbo Yinzhou No.2 Hospital, Ningbo, Zhejiang, China.
BMC Nephrol. 2025 May 22;26(1):253. doi: 10.1186/s12882-025-04179-z.
Sepsis-induced acute kidney injury (S-AKI) is a life-threatening complication of sepsis, marked by dysregulated inflammation, metabolic derangements, and immune dysfunction, driving high mortality. Its multifactorial pathogenesis increasingly implicates DNA methylation-a core epigenetic mechanism-as a critical disease modulator. This review synthesizes current knowledge of DNA methylation in S-AKI, covering molecular mechanisms, cellular dysfunction, and translational potential. In immune cells, sepsis-induced aberrant DNA methylation promotes hypomethylation of pro-inflammatory genes and hypermethylation of anti-inflammatory loci, exacerbating cytokine storms and immunosuppression. In renal tubular epithelial cells, abnormal methylation disrupts apoptosis, oxidative stress responses, and mitochondrial bioenergetics, impairing repair and accelerating S-AKI progression. Renal vascular endothelial cells exhibit methylation-dependent dysregulation of vasoactive and inflammatory pathways, compromising microvascular homeostasis and renal hemodynamics. DNA methylation signatures offer promise as early S-AKI biomarkers, with cell-type-specific patterns reflecting severity, injury, and prognosis. Targeting DNA methyltransferases with epigenetic modifiers represents a novel therapy, though challenges arise from sepsis's complex epigenetic landscape-bidirectional methylation changes, histone crosstalk, and context-dependent responses. A key paradox lies in DNA methylation's dual traits: stability underpinning biomarker reliability and plasticity enabling dynamic inflammatory adaptation, yet introducing therapeutic heterogeneity. Future research should prioritize dissecting cell-specific methylation mechanisms, integrating multi-omics to identify epigenetic subnetworks, and developing real-time monitoring tools for precision diagnosis and tailored interventions. Advancing these frontiers may translate epigenetic insights into transformative strategies to improve outcomes for this devastating condition.
脓毒症诱导的急性肾损伤（S-AKI）是脓毒症一种危及生命的并发症，其特征为炎症调节失调、代谢紊乱和免疫功能障碍，导致高死亡率。其多因素发病机制越来越多地涉及DNA甲基化——一种核心表观遗传机制——作为一种关键的疾病调节因子。本综述综合了目前关于S-AKI中DNA甲基化的知识，涵盖分子机制、细胞功能障碍和转化潜力。在免疫细胞中，脓毒症诱导的异常DNA甲基化促进促炎基因的低甲基化和抗炎基因座的高甲基化，加剧细胞因子风暴和免疫抑制。在肾小管上皮细胞中，异常甲基化破坏细胞凋亡、氧化应激反应和线粒体生物能量学，损害修复并加速S-AKI进展。肾血管内皮细胞表现出血管活性和炎症途径的甲基化依赖性失调，损害微血管稳态和肾血流动力学。DNA甲基化特征有望成为早期S-AKI生物标志物，其细胞类型特异性模式反映严重程度、损伤和预后。用表观遗传修饰剂靶向DNA甲基转移酶代表一种新的治疗方法，尽管脓毒症复杂的表观遗传格局——双向甲基化变化、组蛋白串扰和背景依赖性反应——带来了挑战。一个关键的矛盾在于DNA甲基化的双重特性：稳定性支撑生物标志物的可靠性，可塑性实现动态炎症适应，但也引入了治疗异质性。未来的研究应优先剖析细胞特异性甲基化机制，整合多组学以识别表观遗传子网，并开发实时监测工具以进行精准诊断和量身定制的干预措施。推进这些前沿领域可能将表观遗传学见解转化为变革性策略，以改善这种毁灭性疾病的治疗结果。
