OBJECTIVE: This study aimed to identify genetic variants and their functional consequences underlying Unexplained Recurrent Pregnancy Loss (uRPL) through comprehensive genomic and transcriptomic analyses. METHODS: We recruited 13 Chinese uRPL patients and performed Whole Exome Sequencing (WES) on chorionic villi samples from miscarriage tissues. Additionally, we conducted an integrative analysis using single-cell RNA sequencing data from decidual immune cells to examine expression patterns. RESULTS: WES analysis pinpointed variants in the four MUC genes (MUC4, MUC6, MUC16, and MUC17), six lipid metabolism genes in immune cells (ABCA4, ABCA7, ABCB5, ABCC8, ADGRV1, and ANK3), and two structural genes (PIEZO1 and PKD1), whose variants impair mucosal barriers and lipid homeostasis, thereby leading to immune dysregulation and contributing to uRPL. To delve deeper into the effects of these genetic variants on cellular expression patterns, we undertook an integrative analysis using a single-cell dataset from decidual immune cells in uRPL cases. We observed significant dysregulation of lipid metabolism within immune cells, reduced heat shock protein expression, and enhanced chemokine signaling in uRPL samples, indicating a pro-inflammatory state. CONCLUSIONS: In summary, our study reveals a complex interplay between genetic variants and immune cell dysfunctions in uRPL, emphasizing the role of identified genetic variants in driving pro-inflammatory states. These findings provide a comprehensive view of the molecular mechanisms underlying uRPL, opening paths for novel therapeutic interventions and improved clinical management.