Reduced　glutathione　(GSH)　could　reduce　oxidative　stress　to　improve　adipose　tissue-derived　mesenchymal　stem　cell　(ADSC)　engraftment　efficiency　in　vivo.　However,　the　underlying　mechanisms　remain　unclear.　Our　goal　is　to　investigate　whether　GSH　enhances　ADSC　engraftment　through　targeting　the　TGF　beta/SMAD3/NOX4　pathway.　Liver　fibrotic　male　mice　were　administrated　GSH,　setanaxib　(STX),　and　SIS3　during　ADSC　transplantation.　ADSC　engraftment　efficiency　and　reactive　oxygen　species　(ROS)　level　were　detected　both　in　vivo　and　ex　vivo.　Biochemical　analysis　was　used　to　analyze　the　content　of　superoxide　and　nicotinamide　adenine　dinucleotide　phosphate　oxidases　(NOXs)　in　liver　tissues.　Immunohistochemistry　and　western　blotting　were　used　to　examine　the　protein　level　of　NOX1,　NOX2,　NOX4,　transforming　growth　factor-beta　1　(TGF　beta　1),　SMAD3,　and　p-SMAD3　in　liver　tissues.　Additionally,　the　therapeutic　efficacy　of　the　ADSC　transplantation　was　further　investigated.　We　found　that　GSH　significantly　improved　ADSC　engraftment　efficiency,　which　was　closely　related　to　the　reduced　ROS　generation　in　liver　tissues.　However,　the　enhanced　cell　engraftment　was　abolished　after　the　combined　treatment　with　STX　or　SIS3.　GSH　could　effectively　reduce　superoxide　and　NOXs　content,　and　selectively　inhibit　NOX4　expression　in　liver　tissues.　The　co-localization　results　showed　that　GSH　could　reduce　NOX4　expressed　in　activated　hepatic　stellate　cells.　Mechanistically,　GSH　down-regulated　TGF　beta/SMAD3　signaling.　More　importantly,　GSH　enhanced　the　therapeutic　efficacy　of　ADSC　therapy　in　liver　fibrotic　mice.　Taken　together,　GSH　could　improve　the　engraftment　efficiency　of　ADSCs　in　liver　fibrosis　by　targeting　TGF　beta　1/SMAD3/NOX4　signaling　pathway,　which　provides　a　new　theoretical　basis　for　GSH　enhancing　ADSC　engraftment　efficiency　in　liver　diseases.