Thioredoxin　reductase　1　(TrxR1)　is　over　activity　in　tumor　cell　to　maintain　their　redox　balance.　Although　gold　clusters　have　great　potential　in　antitumor　drug　as　they　could　well　inhibit　TrxR1,　the　molecular　mechanism　has　not　been　disclosed　yet.　In　this　work,　we　revealed　gold　clusters　can　well　inhibit　the　activity　of　TrxR1　in　lung　tumor　cells　and　further　disclosed　the　inhibition　mechanism　by　using　computational　simulation　methods.　We　firstly　inferred　the　binding　sites　of　gold　in　the　hydrophobic　cavities　on　TrxR1.　The　simulation　results　show　that　the　gold　ion　(released　from　Au　cluster)　interact　with　-SH　of　Cys189　in　TrxR1,　this　greatly　increase　the　distance　between　the　C-terminal　redox　center　of　TrxR1　and　the　Trx　redox　center,　thereby　destroy　the　electron　transfer　pathway　between　them.　Our　electron　transfer　destroying　mechanism　is　different　from　the　previous　hypothesis　that　gold　binds　to　the　Sec498　of　TrxR1　which　has　never　been　proved　by　experimental　and　theory　studies.　This　work　provides　a　new　understanding　of　the　gold　clusters　to　inhibit　TrxR1　activity.　(C)　2022　Published　by　Elsevier　B.V.　on　behalf　of　Chinese　Chemical　Society　and　Institute　of　Materia　Medica,　Chinese　Academy　of　Medical　Sciences.