BACKGROUND: Enhancer RNAs (eRNAs) are a group of lncRNAs transcribed from 
enhancers, whose regulatory effects on gene expression are an emerging area of 
interest. However, the role of eRNAs in regulating trophoblast cells and 
unexplained recurrent pregnancy loss (URPL) remains elusive.
METHODS: We profiled eRNAs in villi from URPL patients and matched controls by 
RNA-seq. Functions of URPL-related eRNAs were further investigated in vitro.
RESULTS: We identified lnc-SLC4A1-1, which was transcribed from an active 
enhancer marked with H3K27ac and H3K4me1 and so-called eRNA, highly expressed in 
URPL patients. Gain-of-function experiments indicated that lnc-SLC4A1-1 
facilitated trophoblast cell migration and apoptosis. Mechanistically, as an 
eRNA, lnc-SLC4A1-1 was retained in the nuclei and recruited transcription factor 
NF-κB to bind to CXCL8, resulting in increased H3K27ac in the CXCL8 promoter and 
subsequent elevation of CXCL8 expression. Activation of CXCL8 exacerbated 
inflammatory reactions in trophoblast cells by inducing TNF-α and IL-1β, which 
could be blocked by an antagonist of lnc-SLC4A1-1.
INTERPRETATION: These findings indicate that an eRNA, lnc-SLC4A1-1, alters 
trophoblast function via activation of immune responses and by regulating the 
NF-κB/CXCL8 axis. Our study provides new insights in understanding lncRNA/eRNA 
function in pathological pregnancy, potentially informing on therapeutic 
strategies for URPL. FUND: National Natural Science Foundation of China, Natural 
Science Foundation of Jiangsu Province, National Key Research and Development 
Program, the Priority Academic Program for the Development of Jiangsu Higher 
Education Institutions.