PURPOSE: Recurrent miscarriage (RM) is a distressing and complicated adverse pregnancy outcome. It is commonly recognized that insufficient decidualization could result in RM, but the molecular mechanisms of decidual impairment are still not fully understood. Thus, this study aimed to identify novel key genes potentially involved in RM and explore their roles played in endometrial decidualization. METHODS: Initially, a combinative analysis of decidual and mid-secretory endometrial transcriptomes was performed to discover hub genes involved in the etiology of RM. And the expression levels of hub genes were evaluated in both primary decidual stromal cells (DSCs) and decidual tissues. Subsequently, the immortalized human endometrial cell line, T-HESCs, was used to investigate whether FXYD1 overexpression affects decidualization by regulating Na/K-ATPase activity. RESULTS: FXYD domain containing ion transport regulator 1 (FXYD1) was identified as a hub gene in the pathogenesis of RM through various bioinformatic methods. Abnormally increased FXYD1 expression was observed in DSCs and decidual tissues from RM patients compared to that of the normal group. Furthermore, in vitro decidualization was obviously inhibited by the overexpression of FXYD1. Additionally, Na/K-ATPase activity was significantly elevated during decidualization, whereas overexpression of FXYD1 reduced Na/K-ATPase activity. Bufalin, a Na/K-ATPase inhibitor, showed an effectively inhibitory effect on decidualization. CONCLUSIONS: Collectively, FXYD1 was discovered as a hub gene associated with RM, and its expression levels in RM patients were significantly upregulated. Increased FXYD1 expression might lead to decidualization defects by reducing Na/K-ATPase activity, of which presented a novel prospective treatment target for RM.