PCSK9小干扰RNA疗法在动脉粥样硬化性心血管疾病中的应用OA

Atherosclerotic cardiovascular disease(ASCVD)is a leading cause of morbidity and mortality worldwide;abnormal cholesterol levels constitute a major contributing factor to its onset and progression.Lipid-lowering therapy serves as a critical strategy for both the primary and secondary prevention of ASCVD,with low-density lipoprotein cholesterol(LDL-C)serving as the primary therapeutic target.Statins currently constitute the cornerstone of lipid-lowering therapy;however,their clinical utility is often hampered by issues such as patient intolerance and poor adherence.Consequently,many patients with ASCVD—as well as those at high risk—fail to achieve target lipid levels.Furthermore,statin therapy can inadvertently elevate lipoprotein(a)levels,thereby increasing residual cardiovascular risk.Proprotein convertase subtilisin/kexin type 9(PCSK9)has been demonstrated to exert pleiotropic pro-atherogenic effects,thereby emerging as a novel therapeutic target for the prevention and treatment of ASCVD.This article provides a detailed exposition of the physiological functions of PCSK9,as well as the innovative mechanism of action of Inclisiran—a small interfering RNA(siRNA)therapeutic agent specifically designed to target PCSK9.Given that PCSK9 exerts multifaceted pro-atherogenic effects,Inclisiran operates by utilizing a gene-silencing mechanism to target PCSK9,thereby functionally mimicking the genetic state associated with loss-of-function(LOF)mutations in PCSK9 and inhibiting its synthesis at the source.Furthermore,this article systematically reviews the latest data derived from the ORION series of clinical trials and incorporates recent findings regarding the real-world clinical application of Inclisiran.We also explore the multifaceted anti-atherosclerotic effects of Inclisiran,including its capacity to inhibit endothelial cell pyroptosis and exert anti-inflammatory effects.While Inclisiran's robust cardioprotective profile—coupled with its convenient"twice-yearly"subcutaneous injection regimen—significantly addresses the limitations inherent in conventional therapies,it nonetheless faces certain practical challenges.Specifically,the long-term cardiovascular benefits of Inclisiran remain to be definitively established,and ongoing studies are currently underway to address this question.Moreover,the high cost of the medication,along with concerns regarding its long-term safety profile,represent additional factors that may influence its widespread adoption in future clinical practice.Future research endeavors should therefore focus on evaluating the cost-effectiveness and accessibility of Inclisiran,as well as monitoring its clinical performance within real-world healthcare settings.