{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:16:26Z","timestamp":1788498986719,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901509"],"award-info":[{"award-number":["81901509"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81901509"],"award-info":[{"award-number":["81901509"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015805","name":"Shenzhen Science and Technology Innovation Commission","doi-asserted-by":"publisher","award":["JCYJ20220531095811025, JCYJ20220818103607015"],"award-info":[{"award-number":["JCYJ20220531095811025, JCYJ20220818103607015"]}],"id":[{"id":"10.13039\/501100015805","id-type":"DOI","asserted-by":"publisher"}]},{"award":["JCYJ20220531095811025, JCYJ20220818103607015"],"award-info":[{"award-number":["JCYJ20220531095811025, JCYJ20220818103607015"]}],"id":[{"id":"https:\/\/ror.org\/017n8df75","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Trophoblast invasion is crucial for the establishment of a functional placenta. Defects in this process can cause adverse pregnancy outcomes, such as miscarriage and preeclampsia. Aldo-keto reductase family 1 member B10 (AKR1B10), a key cytoplasmic oxidoreductase that converts retinoids, retinaldehyde isoprenoids, and lipid peroxidation-derived reactive aldehydes into their corresponding alcohols, regulates cell proliferation, inflammation, and metastasis in cancers. Here, our results demonstrated that AKR1B10 is highly expressed in the ectoplacental cone (EPC) of the mouse placenta. Deficiency of AKR1B10 leads to excessive trophoblast giant cell (TGC) invasion, impaired trophoblast cell differentiation of the junctional zone, and accelerated maternal spiral artery remodeling. Mechanistically, loss of AKR1B10 suppressed extracellular regulated protein kinase (ERK) phosphorylation in both murine placentas and human HTR8\/SVneo cells, further promoting HTR8 cell migration and invasion in vitro. Our findings identify AKR1B10 as a critical regulator that restrains trophoblast invasion in the placenta, suggesting it as a new therapeutic target for placental disorders.<\/jats:p>","DOI":"10.3390\/ijms27177728","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aldo-Keto Reductase 1B10 (AKR1B10) Restrains Trophoblast Cell Invasion via the ERK Signaling Pathway"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2400-7763","authenticated-orcid":false,"given":"Suohao","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen 518055, China"},{"name":"Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen 518107, China"},{"name":"Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Cai","sequence":"additional","affiliation":[{"name":"Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8095-9008","authenticated-orcid":false,"given":"Xiaohua","family":"Lei","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen 518107, China"},{"name":"Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8436-9248","authenticated-orcid":false,"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1042\/BJ20051988","article-title":"Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases\/reductases and aldo-keto reductases with retinoids","volume":"399","author":"Gallego","year":"2006","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"217243","DOI":"10.1016\/j.canlet.2024.217243","article-title":"Hepatic stellate cells promote hepatocellular carcinoma development by regulating histone lactylation: Novel insights from single-cell RNA sequencing and spatial transcriptomics analyses","volume":"604","author":"Yu","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22298","DOI":"10.18632\/aging.203538","article-title":"AKR1B10 inhibits the proliferation and migration of gastric cancer via regulating epithelial-mesenchymal transition","volume":"13","author":"Shao","year":"2021","journal-title":"Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.actbio.2019.04.053","article-title":"AKR1B10 (Aldo-keto reductase family 1 B10) promotes brain metastasis of lung cancer cells in a multi-organ microfluidic chip model","volume":"91","author":"Liu","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12935-021-01829-8","article-title":"Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer","volume":"21","author":"Liang","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1158\/0008-5472.CAN-17-2445","article-title":"IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1\/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma","volume":"78","author":"Cheng","year":"2018","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1186\/s12935-024-03623-8","article-title":"Aldo-keto reductase family 1 member B10 prevents esophageal squamous cell carcinoma from reactive carbonyl species-induced cell death and promotes its progression","volume":"24","author":"Li","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13046-026-03653-2","article-title":"AKR1B10 reprograms neutrophils by histone lactylation to foster immune evasion in KRAS(G12C) mutation colorectal cancer liver metastasis","volume":"45","author":"Li","year":"2026","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.1074\/jbc.M707650200","article-title":"Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-\u03b1 in breast cancer cells","volume":"283","author":"Ma","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e70126","DOI":"10.1002\/mco2.70126","article-title":"Depletion of Acetyl-CoA Carboxylase 1 Facilitates Epithelial-Mesenchymal Transition in Prostate Cancer Cells by Activating the MAPK\/ERK Pathway","volume":"6","author":"Lai","year":"2025","journal-title":"MedComm"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/s42003-025-08441-w","article-title":"Exo-miR-1911-5p regulates ferroptosis to promote macrophages M2 polarization-mediated gastric cancer cisplatin resistance via MYB\/AKR1B10\/ACC","volume":"8","author":"Kong","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s41420-022-01135-w","article-title":"LncRNA 1700020I14Rik promotes AKR1B10 expression and activates Erk pathway to induce hepatocyte damage in alcoholic hepatitis","volume":"8","author":"Wu","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/s41419-021-03819-0","article-title":"CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling","volume":"12","author":"Huang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33694","DOI":"10.18632\/oncotarget.16624","article-title":"AKR1B10 promotes breast cancer cell migration and invasion via activation of ERK signaling","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/ame2.12475","article-title":"RNA-seq analysis of mitochondria-related genes regulated by AMPK in the human trophoblast cell line BeWo","volume":"8","author":"Wu","year":"2025","journal-title":"Anim. Models Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6531","DOI":"10.1074\/jbc.M114.610121","article-title":"Aldo-keto Reductase 1B15 (AKR1B15): A MITOCHONDRIAL HUMAN ALDO-KETO REDUCTASE WITH ACTIVITY TOWARD STEROIDS AND 3-KETO-ACYL-CoA CONJUGATES","volume":"290","author":"Weber","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1146\/annurev-genet-120116-024544","article-title":"Genetic Control of Early Cell Lineages in the Mammalian Embryo","volume":"52","author":"Rossant","year":"2018","journal-title":"Annu. Rev. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41421-022-00513-z","article-title":"A differentiation roadmap of murine placentation at single-cell resolution","volume":"9","author":"Jiang","year":"2023","journal-title":"Cell Discov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ydbio.2005.05.010","article-title":"Determinants of trophoblast lineage and cell subtype specification in the mouse placenta","volume":"284","author":"Simmons","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S844","DOI":"10.1016\/j.ajog.2021.11.1356","article-title":"The etiology of preeclampsia","volume":"226","author":"Jung","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1007\/s00018-019-03104-6","article-title":"Human placenta and trophoblast development: Key molecular mechanisms and model systems","volume":"76","author":"Haider","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S745","DOI":"10.1016\/j.ajog.2017.11.577","article-title":"Pathophysiology of placental-derived fetal growth restriction","volume":"218","author":"Burton","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eaav3866","DOI":"10.1126\/sciimmunol.aav3866","article-title":"Gab3 is required for IL-2- and IL-15-induced NK cell expansion and limits trophoblast invasion during pregnancy","volume":"4","author":"Sliz","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.stem.2021.02.025","article-title":"Human naive epiblast cells possess unrestricted lineage potential","volume":"28","author":"Guo","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.stemcr.2018.08.012","article-title":"Dynamic MAPK\/ERK Activity Sustains Nephron Progenitors through Niche Regulation and Primes Precursors for Differentiation","volume":"11","author":"Hirashima","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41586-024-07526-6","article-title":"In vitro reconstitution of epigenetic reprogramming in the human germ line","volume":"631","author":"Murase","year":"2024","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1073\/pnas.0507399103","article-title":"Essential role of B-Raf in ERK activation during extraembryonic development","volume":"103","author":"Matzen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1242\/dev.107409","article-title":"Essential role of the ERK\/MAPK pathway in blood-placental barrier formation","volume":"141","author":"Nadeau","year":"2014","journal-title":"Development"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1242\/dev.031872","article-title":"Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation","volume":"136","author":"Nadeau","year":"2009","journal-title":"Development"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"dev200171","DOI":"10.1242\/dev.200171","article-title":"An integrated atlas of human placental development delineates essential regulators of trophoblast stem cells","volume":"149","author":"Chen","year":"2022","journal-title":"Development"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s41421-024-00740-6","article-title":"A spatiotemporal transcriptomic atlas of mouse placentation","volume":"10","author":"Wu","year":"2024","journal-title":"Cell Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S166","DOI":"10.1016\/S0015-0282(02)03833-5","article-title":"The entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos and trophoblast stem cells (TSC)","volume":"78","author":"Puscheck","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ydbio.2004.07.032","article-title":"Maintenance of mouse trophoblast stem cell proliferation by TGF-\u03b2\/activin","volume":"275","author":"Erlebacher","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ydbio.2004.03.029","article-title":"The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells","volume":"271","author":"Hughes","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1016\/j.jid.2016.03.022","article-title":"The Aldo-Keto Reductase AKR1B10 Is Up-Regulated in Keloid Epidermis, Implicating Retinoic Acid Pathway Dysregulation in the Pathogenesis of Keloid Disease","volume":"136","author":"Jumper","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.cbi.2008.10.027","article-title":"Aldo-keto reductases from the AKR1B subfamily: Retinoid specificity and control of cellular retinoic acid levels","volume":"178","author":"Ruiz","year":"2009","journal-title":"Chem. Biol. Interact."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1006\/dbio.2001.0300","article-title":"Retinoic Acid Promotes Differentiation of Trophoblast Stem Cells to a Giant Cell Fate","volume":"235","author":"Yan","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1158\/1078-0432.CCR-14-2072","article-title":"Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice","volume":"21","author":"Shen","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1042\/BJ20110111","article-title":"Aldo-keto reductase family 1, member B10 is secreted through a lysosome-mediated non-classical pathway","volume":"438","author":"Luo","year":"2011","journal-title":"Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1378\/chest.09-2634","article-title":"Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals","volume":"138","author":"Wang","year":"2010","journal-title":"Chest"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/s42255-023-00775-1","article-title":"A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures","volume":"5","author":"Govaere","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eaba4448","DOI":"10.1126\/scitranslmed.aba4448","article-title":"Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis","volume":"12","author":"Govaere","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"166319","DOI":"10.1016\/j.bbadis.2021.166319","article-title":"Role of AKR1B10 and AKR1B8 in the pathogenesis of non-alcoholic steatohepatitis (NASH) in mouse","volume":"1868","author":"Rajak","year":"2022","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7728\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:27:11Z","timestamp":1788496031000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7728"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":43,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177728"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177728","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}