Abstract

Recurrent spontaneous abortion (RSA) is closely associated with disruption of both immune homeostasis and vascular development at the maternal-fetal interface. To decode the underlying cellular defects, we performed single-cell RNA sequencing (scRNA-seq) on human decidual tissues, revealing a profound imbalance in macrophage polarization and impaired efferocytosis in RSA patients. Through transcriptomic screening and clinical validation, we pinpointed the Fgr proto-oncogene, Src family tyrosine kinase (Fgr) as a key pathological driver overexpressed in RSA macrophages, acting as a molecular brake on the pro-healing M2 phenotype. Seeking a targeted intervention, we demonstrated that the natural flavonoid Apigenin (Api) directly binds and inhibits the Fgr kinase domain, which essentially triggers robust Interleukin 10 (IL10) secretion. Crucially, this Api-mediated Fgr/IL10 signaling axis not only restores M2 polarization and enhances apoptotic cell clearance, but also rescues pro-angiogenic crosstalk with endothelial cells in a vascular endothelial growth factor (VEGF) −dependent manner. Furthermore, in a lipopolysaccharide (LPS)-induced murine miscarriage model, Api administration effectively reduced embryo resorption and rescued pregnancy loss. Collectively, our study highlights the Fgr/IL10 axis as a critical determinant of decidual homeostasis and establishes Api as a promising therapeutic strategy for RSA.