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Recent studies have shown that metabolic abnormalities, including glycolysis inhibition, may dysregulate trophoblast function, leading to URSA. However, the underlying mechanisms remain unclear. Herein, we found that lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, was significantly reduced in the placental villus of URSA patients. The human trophoblast cell line HTR\u20108\/SVneo was used to investigate the possible LDHA\u2010mediated regulation of trophoblast function.\n                    <jats:italic>LDHA<\/jats:italic>\n                    knockdown in HTR\u20108\/SVneo cells induced G0\/G1 phase arrest and increased apoptosis, whereas\n                    <jats:italic>LDHA<\/jats:italic>\n                    overexpression reversed these effects. Next, RNA sequencing combined with Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the PI3K\/AKT signaling pathway is potentially affected by downstream genes of LDHA. Especially, we found that\n                    <jats:italic>LDHA<\/jats:italic>\n                    knockdown decreased the phosphorylation levels of PI3K, AKT, and FOXO1, resulting in a significant downregulation of CyclinD1. In addition, treatment with an AKT inhibitor or FOXO1 inhibitor also verified that the PI3K\/AKT\/FOXO1 signaling pathway influenced the gene expression of CyclinD1 in trophoblast. Moreover, p\u2010AKT expression correlated positively with LDHA expression in syncytiotrophoblasts and extravillous trophoblasts in first\u2010trimester villus. Collectively, this study revealed a new regulatory pathway for LDHA\/PI3K\/AKT\/FOXO1\/CyclinD1 in the trophoblast cell cycle and proliferation.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201219rr","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T10:25:55Z","timestamp":1672395955000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["<scp>LDHA<\/scp>\n                    deficiency inhibits trophoblast proliferation via the\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    \/\n                    <scp>FOXO1<\/scp>\n                    \/\n                    <scp>CyclinD1<\/scp>\n                    signaling pathway in unexplained recurrent spontaneous abortion"],"prefix":"10.1096","volume":"37","author":[{"given":"Yueyue","family":"Zhu","sequence":"first","affiliation":[{"name":"The International Peace Maternity and Child Health Hospital, School of Medicine Shanghai Jiao Tong University  Shanghai China"},{"name":"Shanghai Key Laboratory of Embryo Original Diseases  Shanghai China"},{"name":"Institute of Birth Defects and Rare Diseases, School of Medicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wu","sequence":"additional","affiliation":[{"name":"The International Peace Maternity and Child Health Hospital, School of Medicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Hu","sequence":"additional","affiliation":[{"name":"The International Peace Maternity and Child Health Hospital, School of Medicine Shanghai Jiao Tong University  Shanghai China"},{"name":"Shanghai Key Laboratory of Embryo Original Diseases  Shanghai China"},{"name":"Institute of Birth Defects and Rare Diseases, School of Medicine Shanghai Jiao 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