# Women with polycystic ovary syndrome exhibit impaired endometrial receptivity with excessive ERα and histone lactylation

## TL;DR

Women with polycystic ovary syndrome (PCOS) have reduced fertility due to endometrial issues linked to high ERα and histone lactylation, which could be targeted for treatment.

## Contribution

The study identifies ERα and histone lactylation as key factors in PCOS-related infertility and suggests inhibiting lactate production as a potential therapy.

## Key findings

- Women with PCOS show impaired endometrial receptivity with elevated ERα and histone lactylation.
- Inhibiting histone lactylation in PCOS mice restores uterine receptivity and improves implantation rates.
- ERα and histone lactylation are confirmed as key indicators of endometrial dysfunction in PCOS.

## Abstract

Polycystic ovary syndrome (PCOS) is one of the most common reproductive disorders in women and severely impairs fertility. Extant clinical studies can only provide indirect and plausible evidence to support endometrial dysfunction as an ovary-independent contributor to PCOS infertility, considering heterogeneous confounders in their phenotypes, comorbidities, and severities. By strictly controlling embryonic factors and potential confounders, our retrospective cohort study reports an adverse implantation rate in women with PCOS, confirming abnormalities in the endometrium, which are accompanied by excessive ERα and histone lactylation. Next, we validate the cooccurrence of impaired uterine receptivity with elevated ERα and histone lactylation in the PCOS mouse model. Inhibiting histone lactylation could downregulate ERα and estrogen-responsive genes, restore uterine receptivity, and improve the implantation rate in PCOS mice. Here, we show that upregulated ERα and histone lactylation are key indicators of impaired endometrial receptivity in PCOS, providing a potential therapeutic strategy by inhibiting lactate production.

It remains unclear whether and how endometrial dysfunction leads to infertility in polycystic ovary syndrome (PCOS), independent of the ovary. Here, the authors show that elevated ERα and histone lactylation impair endometrial receptivity in PCOS and serve as potential therapeutic targets.