Placenta-derived Exosomes Mitigate Hypoxia-Induced Trophoblast Apoptosis and Inflammatory Progression via SASH1

Jing Gao; Yongjuan Liu; Ran Zhang; Fangfang Liu; Lixia Wu

doi:10.3791/71083

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Research Article

Placenta-derived Exosomes Mitigate Hypoxia-Induced Trophoblast Apoptosis and Inflammatory Progression via SASH1

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DOI:

10.3791/71083

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August 18th, 2026

Jing Gao^*¹ , Yongjuan Liu^*¹ , Ran Zhang¹ , Fangfang Liu¹ , Lixia Wu¹

¹Department of Obstetrics and Gynecology, The Fourth Hospital of Shijiazhuang

^* These authors contributed equally

Summary

SAM and SH3 domain-containing protein 1 (SASH1) is identified as a key regulator of trophoblast apoptosis and inflammation in pre-eclampsia (PE). Placenta-derived exosomes (P-EXOS) alleviate hypoxia-induced injury by suppressing SASH1 expression. These findings reveal a novel mechanism underlying PE pathogenesis and suggest SASH1 as a potential therapeutic target.

Abstract

SASH1 is a signal adaptor protein involved in cell growth, apoptosis, and immune regulation, and has been increasingly studied in tumor and immune cells. Emerging evidence suggests that SASH1 plays an important role in inflammatory responses and cellular homeostasis, processes that are closely associated with the development of PE. This study aimed to determine whether SASH1 contributes to trophoblast apoptosis and inflammatory responses in PE and whether P-EXOS exerts protective effects through SASH1 regulation. In this study, three PE-related transcriptomic datasets (GSE75010, GSE10588, and GSE60438) were analyzed to identify shared differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Machine learning algorithms were further applied to screen key candidate genes, and single-cell RNA sequencing data were used to characterize cellular heterogeneity in placental tissue and to determine cell type-specific expression patterns. SASH1 was identified as a consensus candidate gene and was significantly upregulated in trophoblast cells from PE samples. In vitro, a hypoxia-treated HTR-8/SVneo trophoblast cell model was established, combined with SASH1 knockdown, SASH1 overexpression, and co-culture with P-EXOS. Functional experiments showed that knockdown of SASH1 significantly suppressed hypoxia-induced trophoblast apoptosis and reduced the secretion of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, whereas SASH1 overexpression promoted apoptosis and inflammatory responses. In addition, P-EXOS treatment markedly reduced SASH1 expression at both mRNA and protein levels and attenuated hypoxia-induced trophoblast injury, while SASH1 overexpression largely abolished these protective effects. Taken together, these findings indicate that SASH1 plays a critical role in trophoblast apoptosis and inflammatory responses in PE. P-EXOS may alleviate hypoxia-induced trophoblastic injury by suppressing SASH1 expression, providing new insights into the molecular mechanisms and potential therapeutic targets for PE.

Introduction

PE is a pregnancy-specific multisystem disorder that typically occurs after 20 weeks of gestation and is clinically characterized by hypertension, proteinuria, and multi-organ dysfunction. It remains a leading cause of maternal and perinatal morbidity and mortality worldwide¹. Despite continuous advances in clinical management, the definitive treatment for PE is still delivery of the placenta, underscoring the incomplete understanding of its pathogenesis and the urgent need to identify novel molecular and cellular mechanisms as well as potential therapeutic targets²^,³.