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Background <p>Polycystic ovary syndrome (PCOS) impairs endometrial receptivity, contributing to reproductive dysfunction. Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear.</p> Objective <p>We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS.</p> Methods <p>Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4’s role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes.</p> Results <p>Phenotypic assessments revealed elevated endometrial Fe<sup>2+</sup> accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates.</p> Conclusion <p>Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.</p>

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The mechanism study of targeting DPP4 in regulating ferroptosis and its influence on endometrial receptivity in PCOS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Jian Zhang,
  • Ruifang Wang,
  • Xiuli Tian,
  • Nan Ding,
  • Yajun He,
  • Kexin Wang,
  • Chengbin Tao,
  • Jiao Cai,
  • Qiliang Jian,
  • Fang Wang

摘要

Background

Polycystic ovary syndrome (PCOS) impairs endometrial receptivity, contributing to reproductive dysfunction. Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear.

Objective

We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS.

Methods

Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4’s role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes.

Results

Phenotypic assessments revealed elevated endometrial Fe2+ accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates.

Conclusion

Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.