# miR-126-5p protects from URSA via inhibiting Caspase-1-dependent pyroptosis of trophoblast cells

## TL;DR

This study shows that miR-126-5p reduces embryo loss in URSA by blocking Caspase-1-driven cell death in placental cells.

## Contribution

The study identifies miR-126-5p as a novel regulator of trophoblast pyroptosis in URSA via Caspase-1/GSDMD signaling.

## Key findings

- miR-126-5p expression is reduced in URSA patients and correlates inversely with CASP1.
- Overexpression of miR-126-5p inhibits Caspase-1/GSDMD signaling and reduces embryo resorption in mice.
- miR-126-5p directly binds to CASP1's 3’-UTR to suppress pyroptosis in trophoblast cells.

## Abstract

Unexplained recurrent spontaneous abortion (URSA) is a distressing pregnancy complication that seriously threat to women's reproductive health. Trophoblast pyroptosis was involved in the occurrence of URSA, but the potential mechanism remains unclear. In this work, we found CASP1 transcription and the level of pyroptosis were significantly elevated in the villous tissues of URSA patients. Suppression of cell pyroptosis by Gasdermin-D (GSDMD) or Caspase-1 inhibitors can reduce embryo resorption rate of URSA mice, while Caspase-1 over-expression in normal pregnant (NP) mice can aggravate embryo resorption. Meanwhile, a pronounced decline in the expression of microRNA-126-5p (miR-126-5p) was found in URSA patients, which was inversely related to CASP1 expression. Over-expression of miR-126-5p restrained trophoblast pyroptosis via inhibiting Caspase-1/GSDMD signaling pathway by direct binding to 3’-UTR of CASP1. Moreover, experiments in vivo substantiated that up-regulation of miR-126-5p effectively suppressed Caspase-1-mediated pyroptosis in placental tissue and significantly reduced embryo resorption rate. Collectively, these results underscored that diminished miR-126-5p expression plays a crucial role in URSA by enhancing trophoblast pyroptosis through activating Caspase-1/GSDMD signaling pathway. As a result, miR-126-5p shows significant promise as a possible biomarker for diagnosis and treatment of URSA.

The online version contains supplementary material available at 10.1007/s00018-025-05713-w.