PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑...PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.展开更多
[目的]综述新近发现的IDOL蛋白(Inducibledegrader of the low-density lipoprotein receptor)对低密度脂蛋白受体(low-densitylipoprotein receptor,LDLR)调节作用及肝X受体(LXR)-IDOL-LDLR轴在脂代谢平衡稳态中作用的研究进展。[方法...[目的]综述新近发现的IDOL蛋白(Inducibledegrader of the low-density lipoprotein receptor)对低密度脂蛋白受体(low-densitylipoprotein receptor,LDLR)调节作用及肝X受体(LXR)-IDOL-LDLR轴在脂代谢平衡稳态中作用的研究进展。[方法]查阅近年来国内外研究IDOL及LXRIDOL通路的相关文献,并归纳总结其在脂代谢中的作用。[结果]IDOL能在转录后水平介导LDLR及其家族其他成员(VLDLR、ApoER2)的泛素化降解,该作用独立于固醇调节元件结合蛋白(SREBP)途径且受LXR的调节。[结论]LXR-IDOL通路能通过IDOL依赖途径泛素化降解LDLR,调节LDLR水平及LDL摄取,从而在脂代谢平衡中发挥重要作用。LXR-IDOL-LDLR轴可能为脂质代谢紊乱及心血管疾病提供新的潜在治疗靶点。展开更多
文摘PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.
文摘[目的]综述新近发现的IDOL蛋白(Inducibledegrader of the low-density lipoprotein receptor)对低密度脂蛋白受体(low-densitylipoprotein receptor,LDLR)调节作用及肝X受体(LXR)-IDOL-LDLR轴在脂代谢平衡稳态中作用的研究进展。[方法]查阅近年来国内外研究IDOL及LXRIDOL通路的相关文献,并归纳总结其在脂代谢中的作用。[结果]IDOL能在转录后水平介导LDLR及其家族其他成员(VLDLR、ApoER2)的泛素化降解,该作用独立于固醇调节元件结合蛋白(SREBP)途径且受LXR的调节。[结论]LXR-IDOL通路能通过IDOL依赖途径泛素化降解LDLR,调节LDLR水平及LDL摄取,从而在脂代谢平衡中发挥重要作用。LXR-IDOL-LDLR轴可能为脂质代谢紊乱及心血管疾病提供新的潜在治疗靶点。
