他汀类药物是最重要的一类药物。在这篇分析综述中，我们阐明了他汀类药物的在靶（靶向 3-羟基-3-甲基戊二酰辅酶 A 还原酶 [HMGCR]）和脱靶效应的复杂分子机制和毒理学原理。他汀类药物与许多膜激酶相互作用，例如表皮生长因子受体（EGFR）、erb-b2受体酪氨酸激酶2（HER2）和MET原癌基因、受体酪氨酸激酶（MET）以及胞质激酶，例如SRC 原癌基因，非受体酪氨酸激酶 (Src)，在纳摩尔浓度下表现出抑制活性。此外，它们在较高浓度下与钙 ATP 酶和过氧化物酶体增殖物激活受体 α (PPARα/NR1C1) 相互作用。他汀类药物与线粒体复合物 III 和 IV 相互作用，其对辅酶 Q10 合成的抑制也会损害复合物 I 和 II 的功能。他汀类药物可作为激酶、钙 ATP 酶和线粒体复合物的抑制剂，同时激活 PPARα。这些脱靶效应可能会导致接受他汀类药物治疗的患者出现副作用，包括肌肉骨骼症状和肝脏影响。有趣的是，他汀类药物的一些脱靶效应也可能是产生良好结果的原因，这与在炎症性疾病和癌症等疾病中重新利用他汀类药物有关。© 2024 作者。约翰·威利出版的《英国药理学杂志》

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.