Defective LCN2–FN1 signaling impairs stromal–immune communication and underlies recurrent implantation failure

Here, we identify significantly reduced LCN2 levels in both mid-luteal endometrial tissue and serum of RIF patients compared to fertile controls. Using uterine-specific conditional knockout (CKO) mouse models, we demonstrate that loss of Lcn2 impairs embryo implantation and reduces pregnancy rates.

Single-cell RNA sequencing of post-implantation uteri on pregnancy day 5 revealed that Lcn2 deficiency reduces the proportion of primary decidual stromal cells and suppresses the proliferation of tissue-resident natural killer (trNK) cells. Mechanistically, we show that stromal-derived LCN2 promotes trNK cell proliferation by activating C/EBPβ-dependent transcription of Fn1. Supplementation with recombinant LCN2 or FN1 restores trNK cell expansion and rescues implantation defects in Lcn2-deficient mice.