PAPSS2-mediated BMPR1A sulfation in stromal cells regulating endometrial decidualization via autophagy

Does 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2)-mediated sulfation contribute to defective decidualization in patients with recurrent implantation failure (RIF), and what are the underlying mechanisms?

Downregulation of PAPSS2 enhances the interaction between bone morphogenetic protein receptor type 1A (BMPR1A) and bone morphogenetic protein 2 (BMP2), as well as SMAD family member 1/5/9 (SMAD1/5/9)-dependent autophagic flux, thereby promoting decidualization and increasing the receptivity of endometrial stromal cells to trophoblast invasion.

Decidualization is essential for embryo implantation and pregnancy maintenance, and impaired decidualization is considered a key pathological mechanism underlying RIF. Although protein tyrosine sulfation is a critical post-translational modification, its role in endometrial decidualization remains unclear.

We integrated transcriptomic datasets, performed in vitro decidualization assays in immortalized human endometrial stromal cells (T-HESCs) and primary human endometrial stromal cells (hEnSCs), and established an artificial decidualization mouse model. Functional assays and molecular analyses were conducted between 2023 and 2026.

Mid-secretory endometrial tissues were collected from patients with RIF and fertile controls. Decidualization was induced in T-HESCs and primary hEnSCs using dibutyryl-cAMP and progesterone. The effects of PAPSS2 knockdown or overexpression were assessed by RT-qPCR, Western blotting, immunoprecipitation, immunofluorescence, and in vitro implantation assays with BeWo spheroids. In vivo, an ovariectomized mouse model was used to evaluate decidualization under pharmacological modulation of BMP-SMAD signaling and autophagy.

We found that sulfation levels were elevated in endometrial stromal cells from RIF patients. Transcriptomic analysis revealed that PAPSS2, a known sulfation-related gene, was consistently downregulated during decidualization. Mechanistically, PAPSS2 knockdown in endometrial stromal cells decreased BMPR1A sulfation, enhanced its binding affinity for BMP2, and activated the downstream SMAD1/5/9 signaling pathway. Functionally, the activation of this pathway promoted autophagy, thereby enhancing decidualization and increasing stromal cell receptivity to trophoblast invasion.

Publicly available bulk transcriptomic datasets GSE75425 and GSE17504, together with the single-cell RNA-seq dataset GSE183837, were obtained from the Gene Expression Omnibus (GEO) database.

Although our data support dysregulated sulfotyrosine levels and implicate the PAPSS2-BMPR1A sulfation axis in stromal decidualization in RIF, further studies with larger sample sizes are required to confirm their in vivo relevance.

Our findings reveal a previously unrecognized mechanism in which the PAPSS2-BMPR1A sulfation axis fine-tunes BMP2/SMAD signaling and autophagy homeostasis to regulate decidualization. This study provides a molecular basis and highlights a potential therapeutic target for uterine factor-related infertility.

This work was supported by the National Key Research and Development Program (No. 2025YFC2708000), the National Natural Science Foundation of China (No. 82371647), the Science Foundation for Outstanding Youth of Liaoning Province (No. 2024JH3/50100023), and the Shenyang Young and Middle-aged Science and Technology Innovation Talents Support Program (No. RC210436).

The authors declare no competing interests.

N/A.