腺苷三磷酸柠檬酸裂解酶（ACLY）是葡萄糖代谢、胆固醇和脂肪酸合成以及炎症级联反应的关键调节酶。Bempedoic acid作为一种ACLY抑制剂，显著降低致动脉粥样硬化的脂质标记物，包括低密度脂蛋白胆固醇（LDL-C）、非高密度脂蛋白胆固醇和载脂蛋白B。ACLY抑制的附加效应还包括抗肿瘤生长、甘油三酯和高敏C-反应蛋白等促炎分子的减少、较低的胰岛素抵抗、肝脏脂生成的减少和体重减轻。虽然已鉴定出许多ACLY抑制剂，但大部分的临床数据都集中在bempedoic acid上。清除胆固醇是一个ACLY抑制方案的III期临床试验系列，评估其对脂质参数的影响和安全性，并于2020年获得了美国食品药品监督管理局的批准。CLEAR结果是一个第三期双盲、随机、安慰剂对照试验，涉及有他汀不耐受史、血清LDL-C水平≥100 mg/dL和心血管疾病史或高风险者。鹾酸柠檬酸酸（bempedoic acid）略微降低了主要的四项心血管复合终点，以及心肌梗塞和冠状血管重建的单独组成部分，但未能降低中风、心血管死亡或全因死亡率。鹾酸柠檬酸（bempedoic acid）导致痛风和胆管结石的发生率更高，并且观察到血清肌酐、尿酸和肝酶水平轻微升高。对于需要进一步降低LDL-C的高风险患者，尤其是那些有他汀不耐受史的患者，采用ACLY抑制剂bempedoic acid已被证实是一种安全有效的治疗方法。最近发表的CLEAR结果试验揭示了bempedoic acid在高风险个体中，与其LDL-C降低程度成比例地减少心血管事件的结果。ACLY抑制的附加效应促使我们更加深入地寻找用于癌症、高甘油三酯血症、慢性炎症、2型糖尿病、脂肪肝病、肥胖症和代谢综合征等疾病的新型ACLY抑制剂。同样，对于在心脏代谢疾病中使用降低脂肪酸合成的治疗方法也正在研究中。

Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss.While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed.ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.