| 37 | 0 | 15 |
| 下载次数 | 被引频次 | 阅读次数 |
目的 通过生物信息学，从铁死亡角度探讨动脉粥样硬化发病机制及相关中药筛选。方法 分别通过高通量基因表达数据库(GEO)、铁死亡数据库(FerrDb)获取动脉粥样硬化、铁死亡相关作用基因。利用“limmar”包筛选出动脉粥样硬化中与铁死亡发生机制相关的差异基因。对动脉粥样硬化铁死亡差异基因进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析。通过最小绝对值收敛和选择算子算法(LASSO)回归筛选出动脉粥样硬化铁死亡关键差异基因，并引入数据集进行验证得到核心基因，再对核心基因进行免疫浸润分析，构建动脉粥样硬化铁死亡核心基因-miRNA网络。最后通过Coremine Medical获取治疗核心基因的相关中药。结果 共筛选得到动脉粥样硬化铁死亡相关差异表达基因109个，其中上调基因55个，下调基因54个。GO与KEGG富集分析结果显示，动脉粥样硬化铁死亡差异基因主要通过程序性细胞死亡、肿瘤坏死因子(TNF)信号通路、白细胞介素(IL)-17信号通路及缺氧诱导因子(HIF)-1信号通路等，发挥调节铁离子结合、铁结合功能。经LASSO回归筛选并验证后得到12个关键基因：磷脂酰肌醇4,5-二磷酸3-激酶催化亚基α(PIK3CA)、高迁移率族蛋白(HMG)B1、组织蛋白酶(CTS)B、DNA连接酶(LIG)3、脂肪细胞增强子结合蛋白(AEBP)2、蛋白酪氨酸磷酸酶非受体(PTPN)6、铁蛋白重链(FTH)1、CDGSH铁硫域蛋白(CISD)1、皮林(PIR)、溶质载体家族16成员(SLC16A)1、核蛋白(NUPR)1、聚ADP-核糖聚合酶家族成员(PARP)12。免疫浸润分析表明，在一定程度上铁死亡所引起的动脉粥样硬化是由多种免疫细胞活化介导的。核心基因-miRNA网络显示，hsa-miR-548x-3p、hsa-miR-607可能是动脉粥样硬化铁死亡发生发展的关键。丹参、黄芩、姜黄、黄芪、柴胡等可作为潜在防治中药。结论 AEBP2、SLC16A1、PIK3CA、HMGB1、CISD1等关键基因是铁死亡介导免疫炎症反应促进动脉粥样硬化进展的核心分子，靶向预测的中药是调节铁死亡治疗动脉粥样硬化的潜在药物。
Abstract：1 Zhu Y,Xian X,Wang Z,et al.Research progress on the relationship between atherosclerosis and inflammation[J].Biomolecules,2018;8(3):80.
2 Ouyang S,You J,Zhi C,et al.Ferroptosis:the potential value target in atherosclerosis[J].Cell Death Dis,2021;12(8):782.
3 Vinchi F,Porto G,Simmelbauer A,et al.Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction[J].Eur Heart J,2020;41(28):2681-95.
4 朱利，吴鸿飞.铁死亡在动脉粥样硬化中的作用及中医药干预研究进展[J].中国实验方剂学杂志，2023;29(2):244-52.
5 Wan X,Zhang H,Tian J,et al.The chains of ferroptosis interact in the whole progression of atherosclerosis[J].J Inflamm Res,2023;16:4575-92.
6 Lin L,Zhang MX,Zhang L,et al.Autophagy,pyroptosis,and ferroptosis:new regulatory mechanisms for atherosclerosis[J].Front Cell Dev Biol,2022;9:809955.
7 Hu H,Chen Y,Jing L,et al.The link between ferroptosis and cardiovascular diseases:a novel target for treatment[J].Front Cardiovasc Med,2021;8:710963.
8 Martinet W,Coornaert I,Puylaert P,et al.Macrophage death as a pharmacological target in atherosclerosis[J].Front Pharmacol,2019;10:306.
9 韩靖，赵国平.促凋亡蛋白Bax和Bak通过Nrf2/GPX4信号通路调控铁死亡[J].生物学杂志，2023;40(3):6-10.
10 Hou W,Xie Y,Song X,et al.Autophagy promotes ferroptosis by degradation of ferritin[J].Autophagy,2016;12(8):1425-8.
11 Kang R,Zeng L,Zhu S,et al.Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis[J].Cell Host Microbe,2018;24(1):97-108.
12 Uyy E,Suica VI,Boteanu RM,et al.Regulated cell death joins in atherosclerotic plaque silent progression[J].Sci Rep,2022;12(1):2814.
13 田嘉珉，陈羽斐，沈伟.M2型巨噬细胞极化及其对动脉粥样硬化的影响[J].临床心血管病杂志，2022;38(10):838-43.
14 徐芳芷，窦琳，沈涛，等.免疫细胞在动脉粥样硬化中的代谢重编程现象[J].中国动脉硬化杂志，2023;31(3):218-24,260.
15 Wang J,Li P,Xu X,et al.MicroRNA-200a inhibits inflammation and atherosclerotic lesion formation by disrupting EZH2-mediated methylation of STAT3[J].Front Immunol,2020;11:907.
16 Kasinath V,Beck C,Sauer P,et al.JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications[J].Science,2021;371(6527):eabc3393.
17 Weng YS,Tseng HY,Chen YA,et al.MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression,cancer stemness and M2 macrophage polarization in triple-negative breast cancer[J].Mol Cancer,2019;18(1):42.
18 Zhao Y,Li M,Yao X,et al.HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications[J].Cell Rep,2020;33(10):108487.
19 Shao W,Wang S,Wang X,et al.miRNA-29a inhibits atherosclerotic plaque formation by mediating macrophage autophagy via PI3K/AKT/mTOR pathway[J].Aging (Albany NY),2022;14(5):2418-31.
20 Shang J,Zhao F,Cao Y,et al.HMGB1 mediates lipopolysaccharide-induced macrophage autophagy and pyroptosis[J].BMC Mol Cell Biol,2023;24(1):2.
21 Filiberto AC,Ladd Z,Leroy V,et al.Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms[J].FASEB J,2022;36(11):e22579.
22 Hua J,Gao Z,Zhong S,et al.CISD1 protects against atherosclerosis by suppressing lipid accumulation and inflammation via mediating Drp1[J].Biochem Biophys Res Commun,2021;577:80-8.
23 颜晓睿，宫丽鸿.从“虚-痰-瘀-毒(热)-风”事件链角度论治冠心病[J].中西医结合心脑血管病杂志，2019;17(13):1985-7.
24 吴瑶，宋囡，贾连群，等.丹参酮ⅡA对ApoE-/-小鼠肝脏脂质沉积及铁死亡相关蛋白表达的影响[J].中国病理生理杂志，2020;36(7):1261-8.
25 Ursini F,Maiorino M.Lipid peroxidation and ferroptosis:the role of GSH and GPx4[J].Free Radic Biol Med,2020;152:175-85.
26 Yuan H,Li X,Zhang X,et al.Identification of ACSL4 as a biomarker and contributor of ferroptosis[J].Biochem Biophys Res Commun,2016;478(3):1338-43.
27 Li M,Meng Z,Yu S,et al.Baicalein ameliorates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via regulating GPX4/ACSL4/ACSL3 axis[J].Chem Biol Interact,2022;366:110137.
28 Xie Y,Song X,Sun X,et al.Identification of baicalein as a ferroptosis inhibitor by natural product library screening[J].Biochem Biophys Res Commun,2016;473(4):775-80.
29 Wei Z,Shaohuan Q,Pinfang K,et al.Curcumin attenuates ferroptosis-induced myocardial injury in diabetic cardiomyopathy through the Nrf2 pathway[J].Cardiovasc Ther,2022;2022:3159717.
30 Sheng S,Xu J,Liang Q,et al.Astragaloside Ⅳ inhibits bleomycin-induced ferroptosis in human umbilical vein endothelial cells by mediating LPC[J].Oxid Med Cell Longev,2021;2021:6241242.
31 黄紫霞，吴明月，许峰，等.柴胡皂苷A通过抑制氧化应激和铁死亡减轻过氧化氢诱导的人脐静脉内皮细胞损伤[J].中国动脉硬化杂志，2022;30(1):43-8.
基本信息:
DOI：
中图分类号:R259
引用信息:
[1]袁一顺,刘中勇,刘言薇等.从铁死亡角度探讨动脉粥样硬化发病机制及相关中药筛选[J].中国老年学杂志,2025,45(11):2561-2569.
基金信息:
国家自然科学基金项目(81960849,82260918); 全国名老中医专家传承工作室建设项目(国中药人教函(2022)7号)