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In Brief: Preeclampsia (PE) is a severe complication that leads to major maternal and fetal mortality and morbidity, and one of its causes is extravillous trophoblast (EVT) dysfunction. This study revealed the role of CD74 in the invasion and proliferation of EVTs., Abstract: PE is a severe hypertensive disorder during pregnancy, and one of its causes is the dysfunction of EVTs. In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data of placentas from PE patients and the sirtuin 1 (SIRT1) heterozygous knockout mouse model, which exhibited typical PE-like symptoms. We identified 134 differentially expressed genes (DEGs) with similar trends in EVTs of PE patients and in parietal trophoblast giant cells (P-TGCs) of Sirt1-/- (HO) placentas from Sirt1+/- (HE) pregnant mice. Interestingly, Kyoto Encyclopedia of Genes and Genomes analysis showed that 134 overlapping genes were related to the MAPK signaling pathway. We validated several DEGs using immunofluorescence at the protein level. Finally, we selected CD74 for further experiments, which showed a decrease in EVTs of PE patients and in P-TGCs of Sirt1-/- placentas from Sirt1+/- pregnant mice. Additionally, cell proliferation assays and transwell assays showed that the proliferation and invasion abilities were decreased in CD74 knockdown HTR8/SVneo cells using lentivirus transfection, which can be improved by adding the SIRT1 agonist SRT1720 or metformin, an agonist of the MAPK signaling pathway. Importantly, the expression of CD74 can be positively regulated by SIRT1. These data suggest that CD74 plays an important protective role in the pathogenesis of preeclampsia by regulating the MAPK signaling pathway, which can be regulated by SIRT1.