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

ABSTRACT: Defective endometrial decidualization and dysregulated immune responses are key contributors to recurrent implantation failure (RIF), yet the underlying molecular mechanisms remain poorly defined. 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. Together, these findings define a previously unrecognized stromal–immune axis in the peri-implantation endometrium and identify LCN2 and FN1 as potential diagnostic markers and therapeutic targets for RIF.

ORGANISM(S): Mus musculus

PROVIDER: GSE303655 | GEO | 2026/06/30

REPOSITORIES: GEO

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

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