AbMole小課堂：從機制到應用，讀懂Nrf2抑制劑ML385核因子E2相關因子2（Nrf2）是細胞內重要的轉錄因子，在調節氧化應激、炎癥反應及細胞代謝等多種生理過程中發揮關鍵作用。ML385（AbMole，M8692）作為一種特異性的Nrf2抑制劑，在科研領域受到廣泛關注。它能夠與Nrf2蛋白特定結構域結合，阻斷Nrf2的激活及相關信號通路的傳導，進而影響細胞的多種生物學功能。一、ML385的作用機制Nrf2是細胞應對氧化應激的關鍵蛋白，在正常生理狀態下，細胞內的氧化還原平衡維持在一定水平，Nrf2與Kelch樣ECH相關蛋白1（Keap1）結合，以無活性形式存在于細胞質中。當細胞受到氧化應激刺激時，Keap1上的某些半胱氨酸殘基發生修飾，導致其與Nrf2的親和力降低，Nrf2得以解離并進入細胞核，與ARE結合啟動基因轉錄。ML385（AbMole，M8692）發揮抑制作用的首要機制是與Nrf2蛋白直接結合。研究發現，ML385能夠特異性地與Nrf2蛋白的Neh2結構域相互作用。Neh2結構域是Nrf2與Keap1結合的關鍵區域，同時也參與Nrf2的核轉位及與DNA的結合過程。ML385與Neh2結構域結合后，可通過空間位阻效應以及改變Neh2結構域的構象，影響Nrf2與Keap1的解離以及Nrf2與ARE的結合能力，從而阻斷Nrf2信號通路的激活。圖SEQ圖\*ARABIC1.Nrf2激活和調節轉錄的經典途徑ADDINEN.CITE<EndNote><Cite><Author>Tonelli</Author><Year>2018</Year><RecNum>334</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>334</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1750039740">334</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Tonelli,C.</author><author>Chio,I.I.C.</author><author>Tuveson,D.A.</author></authors></contributors><auth-address>1ColdSpringHarborLaboratory,ColdSpringHarbor,NewYork. 2LustgartenFoundationPancreaticCancerResearchLaboratory,ColdSpringHarbor,NewYork.</auth-address><titles><title>TranscriptionalRegulationbyNrf2</title><secondary-title>AntioxidRedoxSignal</secondary-title><alt-title>Antioxidants&redoxsignaling</alt-title></titles><periodical><full-title>AntioxidRedoxSignal</full-title><abbr-1>Antioxidants&redoxsignaling</abbr-1></periodical><alt-periodical><full-title>AntioxidRedoxSignal</full-title><abbr-1>Antioxidants&redoxsignaling</abbr-1></alt-periodical><pages>1727-1745</pages><volume>29</volume><number>17</number><edition>2017/09/14</edition><keywords><keyword>Animals</keyword><keyword>*GeneExpressionRegulation</keyword><keyword>Humans</keyword><keyword>NF-E2-RelatedFactor2/*metabolism</keyword><keyword>OxidativeStress/genetics</keyword><keyword>*Transcription,Genetic</keyword><keyword>Nrf2</keyword><keyword>antioxidantresponse</keyword><keyword>transcription</keyword></keywords><dates><year>2018</year><pub-dates><date>Dec10</date></pub-dates></dates><isbn>1523-0864(Print) 1523-0864</isbn><accession-num>28899199</accession-num><urls></urls><custom2>PMC6208165</custom2><electronic-resource-num>10.1089/ars.2017.7342</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]ML385的研究應用ML385用于細胞氧化應激研究在多種細胞模型中，ML385（AbMole，M8692）被廣泛用于研究氧化應激條件下Nrf2信號通路的作用ADDINEN.CITE<EndNote><Cite><Author>Yu</Author><Year>2024</Year><RecNum>125</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>125</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749800723">125</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yu,Xibao</author><author>Wang,Yan</author><author>Tan,Jiaxiong</author><author>Li,Yuchen</author><author>Yang,Pengyue</author><author>Liu,Xuan</author><author>Lai,Jing</author><author>Zhang,Yue</author><author>Cai,Letong</author><author>Gu,Yinfeng</author><author>Xu,Ling</author><author>Li,Yangqiu</author></authors></contributors><titles><title>InhibitionofNRF2enhancestheacutemyeloidleukemiacelldeathinducedbyvenetoclaxviatheferroptosispathway</title><secondary-title>CellDeathDiscovery</secondary-title></titles><periodical><full-title>CellDeathDiscovery</full-title></periodical><pages>35</pages><volume>10</volume><number>1</number><dates><year>2024</year><pub-dates><date>2024/01/18</date></pub-dates></dates><isbn>2058-7716</isbn><urls><related-urls><url>/10.1038/s41420-024-01800-2</url></related-urls></urls><electronic-resource-num>10.1038/s41420-024-01800-2</electronic-resource-num></record></Cite></EndNote>[2]。例如，在人AML細胞系MV4-11、MOLM13中，ML385通過抑制Nrf2信號通路，降低了抗氧化基因（如HO-1、NQO1）的表達，導致細胞內ROS水平持續升高，脂質過氧化增加，從而加劇細胞的氧化損傷ADDINEN.CITE<EndNote><Cite><Author>Yu</Author><Year>2024</Year><RecNum>125</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>125</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749800723">125</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yu,Xibao</author><author>Wang,Yan</author><author>Tan,Jiaxiong</author><author>Li,Yuchen</author><author>Yang,Pengyue</author><author>Liu,Xuan</author><author>Lai,Jing</author><author>Zhang,Yue</author><author>Cai,Letong</author><author>Gu,Yinfeng</author><author>Xu,Ling</author><author>Li,Yangqiu</author></authors></contributors><titles><title>InhibitionofNRF2enhancestheacutemyeloidleukemiacelldeathinducedbyvenetoclaxviatheferroptosispathway</title><secondary-title>CellDeathDiscovery</secondary-title></titles><periodical><full-title>CellDeathDiscovery</full-title></periodical><pages>35</pages><volume>10</volume><number>1</number><dates><year>2024</year><pub-dates><date>2024/01/18</date></pub-dates></dates><isbn>2058-7716</isbn><urls><related-urls><url>/10.1038/s41420-024-01800-2</url></related-urls></urls><electronic-resource-num>10.1038/s41420-024-01800-2</electronic-resource-num></record></Cite></EndNote>[2]。還有研究發現，ML385通過抑制Nrf2/HO-1信號通路，可顯著降低細胞的抗氧化能力，增加脂質過氧化物MDA含量，降低GSH水平ADDINEN.CITEADDINEN.CITE.DATA[3]。ML385用于動物模型氧化應激研究在動物模型研究中，ML385（AbMole，M8692）同樣展現出對氧化應激相關過程的影響。在小鼠脊髓損傷（SCI）模型中，ML385被用作Nrf2抑制劑，以研究Nrf2信號通路在神經保護中的作用。結果表明，ML385顯著削弱了抗氧化劑，如Acacetin（AbMole，M4584），對氧化應激和炎癥的緩解作用，表明Nrf2信號通路在SCI后的抗氧化防御中具有重要作用ADDINEN.CITE<EndNote><Cite><Author>Zhang</Author><Year>2022</Year><RecNum>128</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>128</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749801683">128</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhang,X.</author><author>Xu,L.</author><author>Chen,X.</author><author>Zhou,X.</author><author>Cao,L.</author></authors></contributors><auth-address>DepartmentofOrthopedic,HuangshiCentralHospital,AffiliatedHospitalofHubeiPolytechnicUniversity,EdongHealthcareGroup,No.141TianjinRoad,Huangshi435000,Hubei,China. DepartmentofRadiology,HuangshiCentralHospital,AffiliatedHospitalofHubeiPolytechnicUniversity,EdongHealthcareGroup,Huangshi435000,Hubei,China.</auth-address><titles><title>AcacetinalleviatesneuroinflammationandoxidativestressinjuryviatheNrf2/HO-1pathwayinamousemodelofspinalcordinjury</title><secondary-title>TranslNeurosci</secondary-title></titles><periodical><full-title>TranslNeurosci</full-title></periodical><pages>483-494</pages><volume>13</volume><number>1</number><edition>20221221</edition><keywords><keyword>Ho-1</keyword><keyword>Nrf2</keyword><keyword>acacetin</keyword><keyword>spinalcordinjury</keyword></keywords><dates><year>2022</year><pub-dates><date>Jan1</date></pub-dates></dates><isbn>2081-3856(Print) 2081-6936</isbn><accession-num>36590896</accession-num><urls></urls><custom1>Conflictofinterest:Authorsstatenoconflictofinterest.</custom1><custom2>PMC9773099</custom2><electronic-resource-num>10.1515/tnsci-2022-0266</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[4]。在小鼠腸道氧化應激模型中，ML385被用于研究Nrf2信號通路在緩解氧化應激中的作用。結果顯示，ML385顯著削弱了鞣花酸（AbMole，M2252）對氧化應激的緩解，降低了Nrf2、HO-1和NQO1的表達，增加了MDA水平ADDINEN.CITE<EndNote><Cite><Author>Zhang</Author><Year>2022</Year><RecNum>129</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>129</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749801762">129</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Zhang,X.</author><author>Wang,S.</author><author>Wu,Y.</author><author>Liu,X.</author><author>Wang,J.</author><author>Han,D.</author></authors></contributors><auth-address>StateKeyLaboratoryofAnimalNutrition,CollegeofAnimalScienceandTechnology,ChinaAgriculturalUniversity,Beijing100193,China.</auth-address><titles><title>EllagicAcidAlleviatesDiquat-InducedJejunumOxidativeStressinC57BL/6MicethroughActivatingNrf2MediatedSignalingPathway</title><secondary-title>Nutrients</secondary-title></titles><periodical><full-title>Nutrients</full-title></periodical><volume>14</volume><number>5</number><edition>20220305</edition><keywords><keyword>Animals</keyword><keyword>*Diquat/metabolism/toxicity</keyword><keyword>EllagicAcid/metabolism/pharmacology</keyword><keyword>Jejunum/metabolism</keyword><keyword>Mice</keyword><keyword>Mice,InbredC57BL</keyword><keyword>*NF-E2-RelatedFactor2/genetics/metabolism</keyword><keyword>OxidativeStress</keyword><keyword>SignalTransduction</keyword><keyword>Nrf2</keyword><keyword>diquat</keyword><keyword>ellagicacid</keyword><keyword>jejunum</keyword></keywords><dates><year>2022</year><pub-dates><date>Mar5</date></pub-dates></dates><isbn>2072-6643</isbn><accession-num>35268077</accession-num><urls></urls><custom1>Theauthorsdeclarenoconflictofinterest.</custom1><custom2>PMC8912502</custom2><electronic-resource-num>10.3390/nu14051103</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[5]。抗腫瘤研究ML385（AbMole，M8692）在多種腫瘤模型中展現出顯著的抗腫瘤活性。在NSCLC模型中，ML385對KEAP1突變導致Nrf2功能增強的細胞具有特異性和選擇性ADDINEN.CITEADDINEN.CITE.DATA[6]。此外，ML385還通過抑制PI3K-mTOR信號通路，抑制肺鱗狀細胞癌的生長ADDINEN.CITEADDINEN.CITE.DATA[7]。這些研究表明，ML385可能是一種有前途的腫瘤抑制策略。此外，ML385在研究腫瘤細胞耐藥機制方面也發揮了作用，研究表明，ML385可以通過阻斷Nrf2/HO-1通路來抑制缺氧誘導的乳腺癌細胞（MDA-MB-231）對抑制劑的耐受ADDINEN.CITE<EndNote><Cite><Author>Yang</Author><Year>2025</Year><RecNum>124</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>124</rec-number><foreign-keys><keyapp="EN"db-id="wextdpxe9sewdueavvl5zv97re9rpwdd59dx"timestamp="1749800465">124</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yang,Huan</author><author>Zheng,Wentian</author><author>Lin,Hehua</author><author>Huang,Hanxing</author></authors></contributors><titles><title>ML385SuppressesHypoxia-InducedDrugResistanceandCancerStemnessofBreastCancerCellsbyBlockingtheNrf2/HO-1Pathway</title><secondary-title>PharmaceuticalChemistryJournal</secondary-title></titles><periodical><full-title>PharmaceuticalChemistryJournal</full-title></periodical><pages>1506-1513</pages><volume>58</volume><number>10</number><dates><year>2025</year><pub-dates><date>2025/01/01</date></pub-dates></dates><isbn>1573-9031</isbn><urls><related-urls><url>/10.1007/s11094-025-03301-7</url></related-urls></urls><electronic-resource-num>10.1007/s11094-025-03301-7</electronic-resource-num></record></Cite></EndNote>[8]，ML385還能增強氧化應激損傷和鐵死亡，逆轉腫瘤細胞的耐受性ADDINEN.CITEADDINEN.CITE.DATA[9]。范例詳解首都醫科大學朝陽醫院研究了Sirtuin7（SIRT7）在高血壓小鼠腎臟損傷中的作用及其機制，特別是其在鐵死亡（ferroptosis）、腎纖維化和氧化應激中的調控作用。研究結果表明，SIRT7通過調節KLF15/Nrf2信號通路，減輕高血壓引起的腎臟損傷和功能障礙。在這項研究中，AbMole的ML385（AbMole，M8692）被用來驗證Nrf2是否是SIRT7的關鍵下游靶點ADDINEN.CITEADDINEN.CITE.DATA[10]。最終證實Sirtuin7通過促進KLF15/Nrf2信號傳導減輕高血壓小鼠的腎鐵死亡、纖維化和損傷。圖SEQ圖\*ARABIC2.InhibitionofNrf2byML385antagonizedrhSIRT7mediatedprotectiverolesofferroptosisandpartialEMTinAngⅡ-stimulatedmouserenalTECsADDINEN.CITEADDINEN.CITE.DATA[10]參考文獻及鳴謝ADDINEN.REFLIST[1]C.Tonelli,I.I.C.Chio,D.A.Tuveson,TranscriptionalRegulationbyNrf2,Antioxidants&redoxsignaling29(17)(2018)1727-1745.[2]XibaoYu,YanWang,JiaxiongTan,etal.,InhibitionofNRF2enhancestheacutemyeloidleukemiacelldeathinducedbyvenetoclaxviatheferroptosispathway,CellDeathDiscovery10(1)(2024)35.[3]Y.Liu,Y.Jia,C.Li,etal.,[Dexmedetomidineattenuatesheatstress-inducedoncosisinhumanskeletalmusclecellsbyactivatingtheNrf2/Ho-1pathway],NanFangYiKeDaXueXueBao45(3)(2025)603-613.[4]X.Zhang,L.Xu,X.Chen,etal.,Acacetinalleviatesneuroin