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

Xiaoxiao Zhu^{1 2}, Ke Xu^{1 2}, Shuang Ai³, Yingjie Zhang⁴, Chu Chu^{1 2}, Ran Wei^{1 5}, Shufeng Gao^{1 2}, Lu Liu^{1 2}, Wei Li^{1 2}, Yunhong Zhang^{1 2}, Siambi Kikete⁶, Xinkui Liu^{1 2}, Zhen Zhang^{7 8}, Xia Li^{9 10 11}

Affiliations

¹ Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Changqing District, Jinan, 250399, China.
² Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China.
³ Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
⁴ The First Clinical College of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
⁵ School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
⁶ School of Health Sciences, Department of Pharmacognosy and Pharmaceutical Chemistry, Kenyatta University, Nairobi, 00609, Kenya.
⁷ Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Changqing District, Jinan, 250399, China. 60230133@sdutcm.edu.cn.
⁸ Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China. 60230133@sdutcm.edu.cn.
⁹ Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Changqing District, Jinan, 250399, China. 60230033@sdutcm.edu.cn.
¹⁰ Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China. 60230033@sdutcm.edu.cn.
¹¹ College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China. 60230033@sdutcm.edu.cn.

PMID: 40372489
PMCID: PMC12081782
DOI: 10.1007/s00018-025-05713-w

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.

Keywords: Caspase-1; Pyroptosis; Trophoblast; Unexplained recurrent spontaneous abortion; miR-126-5p.

Cell Mol Life Sci. 2025 May 15;82(1):204.doi: 10.1007/s00018-025-05713-w.

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

Abstract

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