靶向APOC3 siRNA药物在冠心病研究中的进展与展望

Progress and Prospects of APOC3-Targeted siRNA Drugs in Coronary Artery Disease Research

摘要: 冠心病(Coronary Heart Disease, CHD)仍是全球范围内主要致死性心血管疾病之一。尽管以他汀类药物和PCSK9抑制剂为核心的降脂治疗策略显著降低了低密度脂蛋白胆固醇(LDL-C)水平，但相当一部分患者在LDL-C得到充分控制后仍存在显著的心血管事件残余风险。近年来，越来越多的证据表明，甘油三酯及富含甘油三酯脂蛋白(Triglyceride-Rich Lipoproteins, TRLs)在动脉粥样硬化发生发展中发挥独立致病作用。载脂蛋白C-III (Apolipoprotein C-III, APOC3)是甘油三酯代谢通路中的关键调控因子，其通过抑制脂蛋白脂肪酶活性并干扰残余脂蛋白的肝脏清除，促进血浆甘油三酯及动脉粥样硬化性脂蛋白颗粒的蓄积。大量人类遗传学研究一致显示，APOC3功能缺失突变与甘油三酯水平显著降低及冠心病风险下降密切相关，为其作为治疗靶点提供了有力的因果学证据。随着RNA干扰技术的发展，尤其是GalNAc介导的肝靶向递送体系的成熟，靶向APOC3的小干扰RNA (siRNA)药物在疗效、安全性及给药可控性方面展现出显著优势。早期临床研究表明，APOC3-siRNA能够实现持久而显著的甘油三酯及APOC3蛋白降低，并可能通过重塑TRL-残余颗粒代谢通路，为降低甘油三酯相关残余心血管风险提供新的干预策略。本文系统综述了APOC3在冠心病发生发展中的生物学作用、人类遗传学证据以及靶向APOC3的siRNA治疗策略的研究进展，重点讨论其在“后LDL时代”脂质管理中的潜在定位，并总结当前面临的关键挑战与未来研究方向。随着长期随访研究及心血管结局试验的推进，APOC3-siRNA有望成为精准脂质管理和残余心血管风险控制的重要新型治疗手段。

Abstract: Coronary heart disease (CHD) remains one of the major fatal cardiovascular diseases worldwide. Although lipid-lowering treatment strategies based on statins and PCSK9 inhibitors have significantly reduced low-density lipoprotein cholesterol (LDL-C) levels, a considerable proportion of patients still have significant residual cardiovascular event risks even after adequate control of LDL-C. In recent years, more and more evidence has shown that triglycerides and triglyceride-rich lipoproteins (TRLs) play independent pathogenic roles in the development of atherosclerosis. Apolipoprotein C-III (APOC3) is a key regulatory factor in the triglyceride metabolism pathway. It inhibits lipoprotein lipase activity and interferes with the liver clearance of residual lipoproteins, promoting the accumulation of plasma triglycerides and atherosclerotic lipoprotein particles. A large number of human genetic studies have consistently shown that APOC3 functional loss mutations are closely related to significantly reduced triglyceride levels and decreased risk of coronary heart disease, providing strong causal evidence for it as a therapeutic target. With the development of RNA interference technology, especially the mature GalNAc-mediated liver-targeted delivery system, small interfering RNA (siRNA) drugs targeting APOC3 have shown significant advantages in efficacy, safety, and drug delivery controllability. Early clinical studies have shown that APOC3-siRNA can achieve persistent and significant reductions in triglycerides and APOC3 protein, and may provide a new intervention strategy for reducing residual cardiovascular risks related to triglycerides by reshaping the TRL-residual particle metabolic pathway. This article systematically reviews the biological role of APOC3 in the development of coronary heart disease, human genetic evidence, and the research progress of siRNA therapeutic strategies targeting APOC3, focusing on its potential position in lipid management in the “post-LDL era” and summarizing the current key challenges and future research directions. With the advancement of long-term follow-up studies and cardiovascular outcome trials, APOC3-siRNA is expected to become an important new therapeutic approach for precise lipid management and residual cardiovascular risk control.