Temporal control of decidual inflammation by HOXA10 is essential for implantation and its dysregulation is associated with early pregnancy loss.

BACKGROUND

Successful implantation requires tightly regulated endometrial inflammation. While initial inflammatory signaling is essential for implantation, persistent inflammation is detrimental to placentation and pregnancy maintenance. The molecular mechanisms that govern this temporal regulation remain unclear.

OBJECTIVE

To investigate how the transcription factor HOXA10 modulates inflammatory transitions in decidual stromal cells and how its dysregulation contributes to implantation failure and early pregnancy loss.

METHODS

We combined in vitro decidualization of primary human stromal cells with HOXA10 knockdown, transcriptomics, cytokine profiling, and adhesion assays. In parallel, inflammation and fertility were evaluated in Hoxa10 hypomorphic mice. We re-analyzed publicly available bulk and single-cell RNA-seq (scRNA-seq) datasets from human endometrium and first-trimester decidua, focusing on inflammatory decidual stromal cell states to assess the clinical relevance of HOXA10 dysregulation in recurrent pregnancy loss (RPL).

RESULTS

In mice, HOXA10 expression was transiently reduced at implantation but increased post-implantation. Transcriptome profiling revealed that HOXA10 knockdown in decidualized stromal cells induced a pro-inflammatory phenotype along with altered expression of adhesion-related genes and impaired stromal-substrate adhesion. In non-pregnant Hoxa10 hypomorphs, stromal cells showed elevated IL1β and TXNIP expression and activation of the NLRP3-ASC inflammasome, as well as dysregulated receptivity markers. During pregnancy, persistent HOXA10 deficiency prevented resolution of inflammation, leading to abnormal decidual organization and defective placentation. The hypomorphs had infertility or progressive reproductive decline. scRNA-seq of first-trimester human decidua showed that HOXA10 is selectively low in inflammatory decidual stromal cell clusters that exhibit concordant upregulation of IL1B, PYCARD, TXNIP, and inflammasome components. Consistently, in bulk and single-cell datasets from women with recurrent pregnancy loss (RPL), HOXA10 expression was reduced alongside increased inflammatory gene expression.

CONCLUSIONS

HOXA10 acts as a temporal switch that initiates inflammatory activation at implantation but is subsequently required to suppress inflammation, maintain stromal cell adhesion and organization, and support placentation. Loss of this regulatory switch results in persistent decidual inflammation and is associated with pregnancy loss in both mouse models and humans. The preprint version of this article is available at https://doi.org/10.64898/2025.12.02.691844.