Similar articles

Abstract: Ex vivo culture-amplified mesenchymal stem cells (MSCs) have been studied because of their capacity for healing tissue injury. MSC transplantation is a valid approach for promoting the repair of damaged tissues and replacement of lost cells or to safeguard surviving cells, but currently the efficiency of MSC transplantation is constrained by the extensive loss of MSCs during the short post-transplantation period. Hence, strategies to increase the efficacy of MSC treatment are urgently needed. Iron overload, reactive oxygen species deposition, and decreased antioxidant capacity suppress the proliferation and regeneration of MSCs, thereby hastening cell death. Notably, oxidative stress (OS) and deficient antioxidant defense induced by iron overload can result in ferroptosis. ferroptosis may inhibit cell survival after MSC transplantation, thereby reducing clinical efficacy. In this review, we explore the role of ferroptosis in MSC performance. Given that little research has focused on ferroptosis in transplanted MSCs, further study is urgently needed to enhance the in vivo implantation, function, and duration of MSCs.

间充质干细胞移植治疗的新视角：靶向铁死亡通路

[1]BarakatM,HusseinAM,SalamaMF,et al.,2022.Possible underlying mechanisms for the renoprotective effect of retinoic acid-pretreated Wharton’s jelly mesenchymal stem cells against renal ischemia/reperfusion injury.Cells,11(13):1997.

[2]BarrachinaL,CequierA,RomeroA,et al.,2020.Allo-antibody production after intraarticular administration of mesenchymal stem cells (MSCs) in an equine osteoarthritis model: effect of repeated administration, MSC inflammatory stimulation, and equine leukocyte antigen (ELA) compatibility.Stem Cell Res Ther,11:52.

[3]BattagliaAM,ChirilloR,AversaI,et al.,2020.Ferroptosis and cancer: mitochondria meet the “iron maiden” cell death.Cells,9(6):1505.

[4]BhattiFU,MehmoodA,LatiefN,et al.,2017.Vitamin E protects rat mesenchymal stem cells against hydrogen peroxide-induced oxidative stressin vitro and improves their therapeutic potential in surgically-induced rat model of osteoarthritis.Osteoarthritis Cartilage,25(2):321-331.

[5]Bonilla-PorrasAR,Jimenez-Del-RioM,Velez-PardoC,2019.N-acetyl-cysteine blunts 6-hydroxydopamine- and L-buthionine-sulfoximine-induced apoptosis in human mesenchymal stromal cells.Mol Biol Rep,46(4):‍4423-4435.

[6]BrownCW,AmanteJJ,ChhoyP,et al.,2019.Prominin2 drives ferroptosis resistance by stimulating iron export.Dev Cell,51(5):575-586.e4.

[7]BrownK,XieS,QiuXL,et al.,2013.SIRT3 reverses aging-associated degeneration.Cell Rep,3(2):319-327.

[8]BuschhausJM,RajendranS,HumphriesBA,et al.,2022.Effects of iron modulation on mesenchymal stem cell-induced drug resistance in estrogen receptor-positive breast cancer.Oncogene,41(29):3705-3718.

[9]ChenGH,SongCC,PantopoulosK,et al.,2022.Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway.Free Radic Biol Med,180:95-107.

[10]ChenTT,WangHQ,JiangCY,et al.,2021.PKD1 alleviates oxidative stress-inhibited osteogenesis of rat bone marrow-derived mesenchymal stem cells through TAZ activation.J Cell Biochem,122(11):1715-1725.

[11]ChenY,YiX,HuoB,et al.,2022.BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection.Pharmacol Res,177:106122.

[12]ChenZ,JiangJY,FuN,et al.,2022.Targetting ferroptosis for blood cell-related diseases.J Drug Target,30(3):244-258.

[13]ChristidiE,BrunhamLR,2021.Regulated cell death pathways in doxorubicin-induced cardiotoxicity.Cell Death Dis,12(4):339.

[14]ChyauCC,WangHF,ZhangWJ,et al.,2020.Antrodan alleviates high-fat and high-fructose diet-induced fatty liver disease in C57BL/6 mice model via AMPK/Sirt1/SREBP-1c/PPARγ pathway.Int J Mol Sci,21(1):360.

[15]ConradM,PrattDA,2019.The chemical basis of ferroptosis.Nat Chem Biol,15(12):1137-1147.

[16]DengL,ZhouL,ZhuY,et al.,2022.Electroacupuncture enhance therapeutic efficacy of mesenchymal stem cells transplantation in rats with intracerebral hemorrhage.Stem Cell Rev Rep,18(2):570-584.

[17]DenuRA,HemattiP,2016.Effects of oxidative stress on mesenchymal stem cell biology.Oxid Med Cell Longev,2016:2989076.

[18]di PaolaA,PalumboG,TortoraC,et al.,2022.Eltrombopag in paediatric immune thrombocytopenia: iron metabolism modulation in mesenchymal stromal cells.Br J Haematol,197(1):110-119.

[19]DixonSJ,LembergKM,LamprechtMR,et al.,2012.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell,149(5):1060-1072.

[20]DodsonM,Castro-PortuguezR,ZhangDD,2019.NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis.Redox Biol,23:101107.

[21]FanXE,XuMH,RenQF,et al.,2022.Downregulation of fatty acid binding protein 4 alleviates lipid peroxidation and oxidative stress in diabetic retinopathy by regulating peroxisome proliferator-activated receptor γ‍-mediated ferroptosis.Bioengineered,13(4):10540-10551.

[22]FengZ,QinYF,HuoF,et al.,2022.NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury.Biochim Biophys Acta Mol Basis Dis,1868(1):166287.

[23]ForcinaGC,PopeL,MurrayM,et al.,2022.Ferroptosis regulation by the NGLY1/NFE2L1 pathway.Proc Natl Acad Sci USA,119(11):e2118646119.

[24]FuC,WuYF,LiuSJ,et al.,2022.Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia.J Ethnopharmacol,289:115021.

[25]HaaseVH,2021.Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease.Kidney Int Suppl,11(1):8-25.

[26]HamidHA,SarmadiVH,PrasadV,et al.,2022.Electromagnetic field exposure as a plausible approach to enhance the proliferation and differentiation of mesenchymal stem cells in clinically relevant scenarios.J Zhejiang Univ-Sci B (Biomed & Biotechnol),23(1):42-57.

[27]HanL,BaiLL,QuCJ,et al.,2021.PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity.Biochem Biophys Res Commun,576:33-39.

[28]HayashiT,MatsushitaT,HisaharaS,et al.,2022.Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress.J Biochem,171(2):201-213.

[29]HergerN,Bermudez-LekerikaP,FarshadM,et al.,2022.Should degenerated intervertebral discs of patients with modic type 1 changes be treated with mesenchymal stem cells?Int J Mol Sci,23(5):2721.

[30]HuXC,LiRH,WuWJ,et al.,2022.A Fe(III)‍-porphyrin-oxaliplatin(IV) nanoplatform for enhanced ferroptosis and combined therapy.J Control Release,348:660-671.

[31]HushpulianDM,Ammal KaideryN,AhujaM,et al.,2021.Challenges and limitations of targeting the Keap1-Nrf2 pathway for neurotherapeutics: Bach1 de-repression to the rescue.Front Aging Neurosci,13:673205.

[32]JiangJJ,ZhangGF,ZhengJY,et al.,2022.Targeting mitochondrial ROS-mediated ferroptosis by quercetin alleviates high-fat diet-induced hepatic lipotoxicity.Front Pharmacol,13:876550.

[33]JinYH,KatoT,FuruM,et al.,2010.Mesenchymal stem cells cultured under hypoxia escape from senescencevia down-regulation of p16 and extracellular signal regulated kinase.Biochem Biophys Res Commun,391(3):1471-1476.

[34]KhanMA,NagP,GriveiA,et al.,2022.Adenine overload induces ferroptosis in human primary proximal tubular epithelial cells.Cell Death Dis,13(2):104.

[35]KhoshlahniN,SaghaM,MirzapourT,et al.,2020.Iron depletion with deferoxamine protects bone marrow-derived mesenchymal stem cells against oxidative stress-induced apoptosis.Cell Stress Chaperones,25(6):1059-1069.

[36]Kizilay ManciniO,LoraM,CuillerierA,et al.,2018.Mitochondrial oxidative stress reduces the immunopotency of mesenchymal stromal cells in adults with coronary artery disease.Circ Res,122(2):255-266.

[37]KoE,LeeKY,HwangDS,2012.Human umbilical cord blood-derived mesenchymal stem cells undergo cellular senescence in response to oxidative stress.Stem Cells Dev,21(11):1877-1886.

[38]KoH,AnS,AhnS,et al.,2022.Sunscreen filter octocrylene is a potential obesogen by acting as a PPARγ partial agonist.Toxicol Lett,355:141-149.

[39]KorenE,FuchsY,2021.Modes of regulated cell death in cancer.Cancer Discov,11(2):245-265.

[40]LangA,StefanowskiJ,PfeiffenbergerM,et al.,2022.MIF does only marginally enhance the pro-regenerative capacities of DFO in a mouse-osteotomy-model of compromised bone healing conditions.Bone,154:116247.

[41]LeeH,ZandkarimiF,ZhangYL,et al.,2020.Energy-stress-mediated AMPK activation inhibits ferroptosis.Nat Cell Biol,22(2):225-234.

[42]LeeWJ,KimM,ParkHS,et al.,2006.AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARα and PGC-1.Biochem Biophys Res Commun,340(1):291-295.

[43]LeiPX,BaiT,SunYL,2019.Mechanisms of ferroptosis and relations with regulated cell death: a review.Front Physiol,10:139.

[44]LiDL,LiuXM,PiWH,et al.,2022a.Fisetin attenuates doxorubicin-induced cardiomyopathyin vivo andin vitro by inhibiting ferroptosis through SIRT1/Nrf2 signaling pathway activation.Front Pharmacol,12:808480.

[45]LiDL,PiWH,SunZZ,et al.,2022b.Ferroptosis and its role in cardiomyopathy.Biomed Pharmacother,153:113279.

[46]LiXC,ZengJY,LiuYP,et al.,2020.Inhibitory effect and mechanism of action of quercetin and quercetin diels-alderanti-dimer on erastin-induced ferroptosis in bone marrow-derived mesenchymal stem cells.Antioxidants,9(3):205.

[47]LiXH,LiC,TangYT,et al.,2018.NMDA receptor activation inhibits the antifibrotic effect of BM-MSCs on bleomycin-induced pulmonary fibrosis.Am J Physiol Lung Cell Mol Physiol,315(3):L404-L421.

[48]LiXL,TianXY,LiuTL,et al.,2022.Hydroxytyrosol alleviated hypoxia-mediated PC12 cell damage through activating PI3K/AKT/mTOR-HIF-1α signaling.Oxid Med Cell Longev,2022:8673728.

[49]LiY,JinDX,XieWX,et al.,2018.PPAR-γ and Wnt regulate the differentiation of MSCs into adipocytes and osteoblasts respectively.Curr Stem Cell Res Ther,13(3):185-192.

[50]LiangZW,WuQ,WangHL,et al.,2022.Silencing of lncRNA MALAT1 facilitates erastin-induced ferroptosis in endometriosis through miR-145-5p/MUC1 signaling.Cell Death Discov,8:190.

[51]LignittoL,LeboeufSE,HomerH,et al.,2019.Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1.Cell,178(2):316-329.e18.

[52]LimJ,HeoJ,JuH,et al.,2020.Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway.Sci Adv,6(16):eaba1334.

[53]LinDJ,ZhouLP,WangB,et al.,2017.Overexpression of HIF-1α in mesenchymal stem cells contributes to repairing hypoxic-ischemic brain damage in rats.C R Biol,340(1):18-24.

[54]LinXY,PingJY,WenY,et al.,2020.The mechanism of ferroptosis and applications in tumor treatment.Front Pharmacol,11:1061.

[55]LiuJ,KuangFM,KroemerG,et al.,2020.Autophagy-dependent ferroptosis: machinery and regulation.Cell Chem Biol,27(4):420-435.

[56]LiuJ,RenZX,YangL,et al.,2022.The NSUN5-FTH1/FTL pathway mediates ferroptosis in bone marrow-derived mesenchymal stem cells.Cell Death Discov,8:99.

[57]LiuLG,LiY,CaoDY,et al.,2021.SIRT3 inhibits gallbladder cancer by induction of AKT-dependent ferroptosis and blockade of epithelial-mesenchymal transition.Cancer Lett,510:93-104.

[58]LiuM,KongXY,YaoY,et al.,2022.The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review.Ann Transl Med,10(6):368.

[59]LiuMY,LiHM,WangXY,et al.,2022.TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway.Free Radic Biol Med,182:219-231.

[60]LiuYQ,GuW,2022.p53 in ferroptosis regulation: the new weapon for the old guardian.Cell Death Differ,29(5):895-910.

[61]LuDB,ZhangL,WangHH,et al.,2012.Peroxisome proliferator-activated receptor-‍γ coactivator-1α (PGC-1α) enhances engraftment and angiogenesis of mesenchymal stem cells in diabetic hindlimb ischemia.Diabetes,61(5):1153-1159.

[62]LuWY,ZhaoMF,RajbhandaryS,et al.,2013.Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cellsin vitro and suppresses hematopoiesis in iron overload patients.Eur J Haematol,91(3):249-261.

[63]MaJJ,ShiXX,LiMJ,et al.,2022.MicroRNA-181a-2-3p shuttled by mesenchymal stem cell-secreted extracellular vesicles inhibits oxidative stress in Parkinson’s disease by inhibiting EGR1 and NOX4.Cell Death Discov,8:33.

[64]MaT,WuJH,MuJF,et al.,2022.Biomaterials reinforced MSCs transplantation for spinal cord injury repair.Asian J Pharm Sci,17(1):4-19.

[65]Macías-RodríguezRU,InzaugaratME,Ruiz-MargáinA,et al.,2020.Reclassifying hepatic cell death during liver damage: ferroptosis—a novel form of non-apoptotic cell death?Int J Mol Sci,21(5):1651.

[66]MaoZY,HineC,TianX,et al.,2011.SIRT6 promotes DNA repair under stress by activating PARP1.Science,332(6036):1443-1446.

[67]MengSS,XuXP,ChangW,et al.,2018.LincRNA-p21 promotes mesenchymal stem cell migration capacity and survival through hypoxic preconditioning.Stem Cell Res Ther,9:280.

[68]MiaoY,ChenYW,XueF,et al.,2022.Contribution of ferroptosis and GPX4’s dual functions to osteoarthritis progression.eBioMedicine,76:103847.

[69]MinagawaS,YoshidaM,ArayaJ,et al.,2020.Regulated necrosis in pulmonary disease. A focus on necroptosis and ferroptosis.Am J Respir Cell Mol Biol,62(5):554-562.

[70]MohammadiS,BarzegariA,DehnadA,et al.,2021.Astaxanthin protects mesenchymal stem cells from oxidative stress by direct scavenging of free radicals and modulation of cell signaling.Chem Biol Interact,333:109324.

[71]MunnurD,AhelI,2017.Reversible mono-ADP-ribosylation of DNA breaks.FEBS J,284(23):4002-4016.

[72]NiS,YuanY,QianZ,et al.,2021.Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis.Free Radic Biol Med,169:271-282.

[73]NishizawaH,YamanakaM,IgarashiK,2022.Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal.FEBS J, online.

[74]NoubariZO,GolchinA,FathiM,et al.,2022.Designing robust chitosan-based hydrogels for stem cell nesting under oxidative stress.BioImpacts,12(1):57-64.

[75]OrcianiM,GorbiS,BenedettiM,et al.,2010.Oxidative stress defense in human-skin-derived mesenchymal stem cells versus human keratinocytes: different mechanisms of protection and cell selection.Free Radic Biol Med,49(5):830-838.

[76]PandrangiSL,ChittineediP,ChikatiR,et al.,2022.Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer.Am J Cancer Res,12(3):974-985.

[77]ParkEJ,ParkYJ,LeeSJ,et al.,2019.Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells.Toxicol Lett,303:55-66.

[78]ParkSY,JeongAJ,KimGY,et al.,2017.Lactoferrin protects human mesenchymal stem cells from oxidative stress-induced senescence and apoptosis.J Microbiol Biotechnol,27(10):1877-1884.

[79]PatelS,KhanH,MajumdarA,2022.Crosstalk between sirtuins and Nrf2: SIRT1 activators as emerging treatment for diabetic neuropathy.Metab Brain Dis,37(7):2181-2195.

[80]PeyvandiAA,AbbaszadehHA,RoozbahanyNA,et al.,2018.Deferoxamine promotes mesenchymal stem cell homing in noise-induced injured cochlea through PI3K/AKT pathway.Cell Prolif,51(2):e12434.

[81]PoursaitidisI,WangXM,CrightonT,et al.,2017.Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine.Cell Rep,18(11):2547-2556.

[82]QuL,HeXY,TangQ,et al.,2022.Iron metabolism, ferroptosis, and lncRNA in cancer: knowns and unknowns. J Zhejiang Univ-Sci B (Biomed & Biotechnol),23(10):844-862.

[83]RanQC,YuYL,ChenWZ,et al.,2018.Deferoxamine loaded titania nanotubes substrates regulate osteogenic and angiogenic differentiation of MSCsvia activation of HIF-1α signaling.Mater Sci Eng C,91:44-54.

[84]Rodríguez-GracianiKM,Chapa-DubocqXR,Ayala-ArroyoEJ,et al.,2022.Effects of ferroptosis on the metabolome in cardiac cells: the role of glutaminolysis.Antioxidants,11(2):278.

[85]ShaoFJ,LiuR,TanX,et al.,2022.MSC transplantation attenuates inflammation, prevents endothelial damage and enhances the angiogenic potency of endogenous MSCs in a model of pulmonary arterial hypertension.J Inflamm Res,15:2087-2101.

[86]ShatrovaAN,BurovaEB,KharchenkoMV,et al.,2021.Outcomes of deferoxamine action on H₂O₂-induced growth inhibition and senescence progression of human endometrial stem cells.Int J Mol Sci,22(11):6035.

[87]ShenYY,ZhengCJ,TanYP,et al.,2018.MagA increases MRI sensitivity and attenuates peroxidation-based damage to the bone-marrow haematopoietic microenvironment caused by iron overload.Artif Cells Nanomed Biotechnol,46(sup3):S18-S27.

[88]ShiYJ,ZhangXL,WanZH,et al.,2022.Mesenchymal stem cells against intestinal ischemia-reperfusion injury: a systematic review and meta-analysis of preclinical studies.Stem Cell Res Ther,13:216.

[89]SongQX,PengSX,CheFY,et al.,2022.Artesunate induces ferroptosis via modulation of p38 and ERK signaling pathway in glioblastoma cells.J Pharmacol Sci,148(3):300-306.

[90]SongYH,WuZY,XueH,et al.,2022.Ferroptosis is involved in regulating perioperative neurocognitive disorders: emerging perspectives.J Neuroinflammation,19(1):219.

[91]StaffNP,JonesDT,SingerW,2019.Mesenchymal stromal cell therapies for neurodegenerative diseases.Mayo Clin Proc,94(5):892-905.

[92]SuLJ,ZhangJH,GomezH,et al.,2019.Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis.Oxid Med Cell Longev,2019:5080843.

[93]SuYW,ZhaoB,ZhouLF,et al.,2020.Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs.Cancer Lett,483:127-136.

[94]SunHL,WuYR,FuDJ,et al.,2014.SIRT6 regulates osteogenic differentiation of rat bone marrow mesenchymal stem cells partially via suppressing the nuclear factor-‍κB signaling pathway.Stem Cells,32(7):1943-1955.

[95]SvenssonS,PalmerM,SvenssonJ,et al.,2022.Monocytes and pyrophosphate promote mesenchymal stem cell viability and early osteogenic differentiation.J Mater Sci Mater Med,33:11.

[96]TanYW,HuangY,MeiR,et al.,2022.HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis.Cell Death Dis,13(4):319.

[97]TangR,XuJ,ZhangB,et al.,2020.Ferroptosis, necroptosis, and pyroptosis in anticancer immunity.J Hematol Oncol,13:110.

[98]TatoneC,di EmidioG,BarbonettiA,et al.,2018.Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility.Hum Reprod Update,24(3):267-289.

[99]TeliP,KaleV,VaidyaA,2022.Mesenchymal stromal cells-derived secretome protects Neuro-2a cells from oxidative stress-induced loss of neurogenesis.Exp Neurol,354:114107.

[100]VancuraA,NagarS,KaurP,et al.,2018.Reciprocal regulation of AMPK/SNF1 and protein acetylation.Int J Mol Sci,19(11):3314.

[101]Villalón-GarcíaI,Álvarez-CórdobaM,Povea-CabelloS,et al.,2022.Vitamin E prevents lipid peroxidation and iron accumulation inPLA2G6-associated neurodegeneration.Neurobiol Dis,165:105649.

[102]WangC,LiuT,TongYM,et al.,2021.Ulinastatin protects against acetaminophen-induced liver injury by alleviating ferroptosis via the SIRT1/NRF2/HO-1 pathway.Am J Transl Res,13(6):6031-6042.

[103]WangCF,WangYT,ShenL,2021.Mitochondrial proteins in heart failure: the role of deacetylation by SIRT3.Pharmacol Res,172:105802.

[104]WangD,XieY,PengHQ,et al.,2022.LPS preconditioning of MSC-CM improves protection against hypoxia/reoxygenation-induced damage in H9c2 cells partly via HMGB1/Bach1 signalling.Clin Exp Pharmacol Physiol,49(12):1319-1333.

[105]WangLJ,LeeYC,ChiouJT,et al.,2022.Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF-α expression in hydroquinone-treated leukemia cells.Cell Biol Toxicol, online.

[106]WangS,LeiBY,ZhangE,et al.,2022.Targeted therapy for inflammatory diseases with mesenchymal stem cells and their derived exosomes: from basic to clinics.Int J Nanomed,17:1757-1781.

[107]WangY,ZhangMH,BiR,et al.,2022.ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury.Redox Biol,51:102262.

[108]XieYC,ZhuS,SongXX,et al.,2017.The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity.Cell Rep,20(7):1692-1704.

[109]XuJF,ZhangMH,LiuF,et al.,2021.Mesenchymal stem cells alleviate post-resuscitation cardiac and cerebral injuries by inhibiting cell pyroptosis and ferroptosis in a swine model of cardiac arrest.Front Pharmacol,12:793829.

[110]YangF,YangL,LiY,et al.,2017.Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence.J Pineal Res,63(3):e12422.

[111]YangL,FanM,DuF,et al.,2012.Hypoxic preconditioning increases iron transport rate in astrocytes.Biochim Biophys Acta Mol Basis Dis,1822(4):500-508.

[112]YangM,TsuiMG,TsangJKW,et al.,2022.Involvement of FSP1-CoQ₁₀-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis.Cell Death Dis,13(5):468.

[113]YangYW,YuXW,ZhangY,et al.,2018.Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury.Clin Sci,132(7):825-838.

[114]YaoXD,JingXZ,GuoJC,et al.,2019.Icariin protects bone marrow mesenchymal stem cells against iron overload induced dysfunction through mitochondrial fusion and fission, PI3K/AKT/mTOR and MAPK pathways.Front Pharmacol,10:163.

[115]YuM,YuJY,YiYF,et al.,2022.Oxidative stress-amplified nanomedicine for intensified ferroptosis-apoptosis combined tumor therapy.J Control Release,347:104-114.

[116]YuanHF,ZhaiC,YanXL,et al.,2012.SIRT1 is required for long-term growth of human mesenchymal stem cells.J Mol Med,90(4):389-400.

[117]YuanSY,WeiC,LiuGF,et al.,2022.Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF-1α/SLC7A11 pathway.Cell Prolif,55(1):e13158.

[118]YucelC,ArslanFD,EkmekciS,et al.,2019.Protective effect of all-trans retinoic acid in cisplatin-induced testicular damage in rats.World J Mens Health,37(2):249-256.

[119]ZhaiQY,RenYQ,NiQS,et al.,2022.Transplantation of human umbilical cord mesenchymal stem cells-derived neural stem cells pretreated with neuregulin1β ameliorate cerebral ischemic reperfusion injury in rats.Biomolecules,12(3):428.

[120]ZhangL,MaXJN,FeiYY,et al.,2022a.Stem cell therapy in liver regeneration: focus on mesenchymal stem cells and induced pluripotent stem cells.Pharmacol Ther,232:108004.

[121]ZhangL,LiY,DongYC,et al.,2022b.Transplantation of umbilical cord-derived mesenchymal stem cells promotes the recovery of thin endometrium in rats.Sci Rep,12:412.

[122]ZhangXQ,LiXG,2022.Abnormal iron and lipid metabolism mediated ferroptosis in kidney diseases and its therapeutic potential.Metabolites,12(1):58.

[123]ZhangXQ,LiLXY,DingH,et al.,2021.Ferroptosis promotes cyst growth in autosomal dominant polycystic kidney disease mouse models.J Am Soc Nephrol,32(11):2759-2776.

[124]ZhangYC,LiLQ,LiYN,et al.,2022.An ROS-activatable nanoassembly remodulates tumor cell metabolism for enhanced ferroptosis therapy.Adv Healthc Mater,11(2):2101702.

[125]ZhouBJ,GeTT,ZhouLP,et al.,2020.Dimethyloxalyl glycine regulates the HIF-1 signaling pathway in mesenchymal stem cells.Stem Cell Rev Rep,16(4):702-710.

[126]ZhouH,ZhouYL,MaoJA,et al.,2022.NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells.Redox Biol,55:102413.

[127]ZhouZM,BaoJP,PengX,et al.,2022.Small extracellular vesicles from hypoxic mesenchymal stem cells alleviate intervertebral disc degeneration by delivering miR-17-5p.Acta Biomater,140:641-658.

[128]ZhuZY,LiuYD,GongY,et al.,2022.Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of Alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis.Acta Pharmacol Sin,43:39-49.