近日，四川大学袁慧军小组揭示了体内表观基因组编辑降低小鼠循环脂质并减轻动脉粥样硬化。相关论文于2026年4月13日发表在《遗传学报》杂志上。

课题组开发了通过腺相关病毒或脂质纳米颗粒递送的CRISPRoff平台，以表观遗传方式在体内沉默肝脏Hmgcr或Pcsk9。在C57BL/6J野生型和ApoE/在小鼠中，CRISPRoff介导这些靶标的持久抑制，导致循环总胆固醇、低密度脂蛋白胆固醇和甘油三酯的显著降低。在ApoE/背景下，Pcsk9的表观遗传沉默赋予明显的血管保护，包括减少肝脏和主动脉根部的脂质积累，减少坏死核心形成，减少巨噬细胞浸润，增强斑块稳定性。总之，这些结果提供了基于CRISPRoff的表观基因组编辑能够稳定抑制临床相关靶点并改善动脉粥样硬化疾病关键特征的原理证明。这项工作为表观遗传调控在心血管疾病中的广泛治疗应用奠定了基础。

据悉，动脉粥样硬化性心血管疾病仍然是全球死亡的主要原因，高胆固醇血症是动脉粥样硬化发生的关键驱动因素。尽管目前的降脂疗法显著改善了循环脂质谱，但仍需要提供更持久、安全、有效的脂质代谢控制策略。表观基因组编辑为在不改变潜在DNA序列的情况下长期抑制疾病修饰基因提供了一种有前途的方法。

附：英文原文

Title: In vivo epigenome editing reduces circulating lipids and attenuates atherosclerosis in mice

Author: Yingjie Zhang , Huijun Yuan

Issue&Volume: 2026/04/13

Abstract: Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE/ mice, CRISPRoff mediates robust and durable repression of these targets, leading to marked reductions in circulating total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In the ApoE/ context, epigenetic silencing of Pcsk9 confers pronounced vascular protection, including decreased lipid accumulation in the liver and aortic root, reduced necrotic core formation, diminished macrophage infiltration, and enhanced plaque stability. Together, these results provide proof of principle that CRISPRoff-based epigenome editing enables stable repression of clinically relevant targets and ameliorates key features of atherosclerotic disease. This work lays the foundation for broader therapeutic applications of epigenetic modulation in cardiovascular disorders.

DOI: 10.1016/j.jgg.2026.04.004

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852726001323