BRD4 Inhibitor Alleviates Recurrent Spontaneous Abortion via Regulating BRD4/STAT3/IL‐17A Axis to Decrease the Th17 Cell Differentiation

TL;DR

A BRD4 inhibitor reduces spontaneous abortion by blocking Th17 cell development through a molecular pathway involving BRD4, STAT3, and IL-17A.

Contribution

This study reveals a novel mechanism by which BRD4 inhibition alleviates RSA via the BRD4/STAT3/IL-17A axis and Th17 cell suppression.

Findings

BRD4 inhibition reduces Th17 cell differentiation and IL-17A expression in RSA patients.

BETi treatment decreases embryo absorption in a mouse model of RSA.

BRD4 binds to STAT3, and its inhibition disrupts STAT3-mediated IL-17A transcription.

Abstract

Recurrent spontaneous abortion (RSA) is an abnormal phenomenon that severely affects women's quality of life. Inhibiting Th17 cell differentiation can alleviate RSA. This research explored the mechanism by which BRD4 Inhibitor (BETi) suppressed the differentiation of Th17 cells to mitigate RSA.

PBMCs and Naive CD4+ T cells were induced to differentiate into Th17 and Treg cells. An abortion‐prone pregnancy mouse model was constructed by intraperitoneal injection of lipopolysaccharide. The Th17/Treg ratio was determined by flow cytometry. The association between STAT3 and IL‐17A promoter was investigated by ChIP and dual luciferase assays. Co‐IP and yeast two‐hybrid assays were used to determine BRD4 binding to STAT3. The markers of Th17/Treg cell differentiation and lipid synthesis were checked by ELISA, IHC, RT‐qPCR, and Western blot.

The Th17/Treg ratio and the expression levels of BRD4, STAT3, and IL‐17A were elevated, while STAT5b expression was down‐regulated in RSA patients. BETi or STAT3 knockdown decreased the differentiation of Th17 cells and lipid synthesis. BRD4 inhibition impaired STAT3‐mediated IL‐17A transcription. BETi inhibited embryo absorption in mice.

BETi inhibits the differentiation of Th17 cells in RSA by reducing the STAT3‐mediated IL‐17A expression.

The collective findings suggest that BETi inhibits STAT3 expression to decrease IL‐17A transcription by targeting BRD4, which hinders Th17 cell differentiation and ultimately alleviates RSA.

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