# HRS Degradation‐Induced Nicotinamide Deficiency in Placental Extracellular Vesicles Triggers Preeclampsia by Disrupting Maternal‐Fetal Immune Homeostasis

## TL;DR

Low nicotinamide in placental vesicles from preeclampsia disrupts immune balance, leading to disease symptoms.

## Contribution

Identifies HRS degradation and nicotinamide deficiency in placental extracellular vesicles as a novel mechanism in preeclampsia.

## Key findings

- Nicotinamide levels in preeclampsia-derived extracellular vesicles are lower and correlate with disease severity.
- Reduced nicotinamide in these vesicles impairs inhibition of Th1 and Th17 immune cells, causing preeclampsia-like symptoms.
- HRS degradation via HSP27 in trophoblasts reduces nicotinamide loading into extracellular vesicles.

## Abstract

Preeclampsia (PE) is closely associated with alterations in placental extracellular vesicles (pEVs), but the mechanisms and their role in PE pathogenesis remain unclear. This study reveals that nicotinamide (NAM) levels in PE‐derived pEVs (PE‐EVs) are lower than in pEVs from normal pregnancies, correlating with disease severity. Functionally, NAM in pEVs inhibits Th1 differentiation via SIRT1 suppression and Th17 differentiation via macrophages. NAM‐deficient pEVs exhibit reduced capacity to inhibit Th1 and Th17 cell differentiation both in vitro and in vivo, leading to PE‐like symptoms. NAM is enriched in pEVs compared to placental villous tissue and maternal serum. The lower NAM in PE‐EVs is due to decreased hepatocyte growth factor‐regulated tyrosine kinase substrate (HRS) expression in trophoblasts, which loads NAM into the cargo of multivesicular bodies (MVBs) via binding to the tryptophan‐115 residue of HRS. Furthermore, the reduction of HRS in PE trophoblasts results from ubiquitination and degradation by elevated HSP27. Collectively, these findings indicate that elevated HSP27 in PE trophoblasts leads to the degradation of HRS, a reduction in pEV NAM levels, and diminished Th1 and Th17 inhibitory effects, thereby contributing to the development of PE.

This study shows that lower NAM levels in PE‐derived pEVs correlate with disease severity. NAM‐deficient pEVs reduce Th1 and Th17 inhibition, leading to PE‐like symptoms. NAM in pEVs inhibits Th1 via SIRT1 and Th17 via macrophages. Reduced NAM in PE‐EVs is due to decreased HRS expression in trophoblasts, resulting from elevated HSP27. These changes contribute to PE development.