L-(+)-Ergothioneine ameliorates preeclampsia-associated vascular endothelial dysfunction by modulating the Nrf2-PPARγ-sFlt-1 axis.

Abstract

BACKGROUND: Preeclampsia (PE) is a serious complication of pregnancy, with vascular endothelial dysfunction being a core pathological feature. This study aimed to investigate whether L-(+)-ergothioneine (LET) ameliorates PE-associated endothelial dysfunction by regulating the Nrf2-PPARγ-sFlt-1 axis. METHODS: A LPS-induced trophoblast dysfunction model was established using lipopolysaccharide (LPS)-induced human trophoblast cells (HTR8/SVneo). Techniques including CCK-8 assay, flow cytometry, wound healing assay, ELISA, qPCR, Western blot, and immunofluorescence were employed to assess the effects of LET on cell viability, apoptosis, invasion, inflammatory cytokine levels, and the expression of key molecules in the signaling pathway. RESULTS: LET significantly increased the viability of LPS-induced trophoblasts, promoted migration, inhibited apoptosis, and downregulated pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and endothelial dysfunction markers (sFlt-1, ET-1, PAI-1), while upregulating the anti-inflammatory cytokine IL-4 and plasminogen activators (tPA, uPA). Mechanistically, LET inhibited Nrf2 nuclear translocation and promoted PPARγ expression, consequently reducing sFlt-1 levels. The protective effects of LET were mimicked by the PPARγ activator pioglitazone and reversed by the inhibitor FX-909. Furthermore, the supernatant from LET-treated trophoblasts promoted the viability and invasion of human umbilical vein endothelial cells (HUVECs). CONCLUSIONS: L-(+)-Ergothioneine improves trophoblast function and indirectly promotes endothelial recovery by modulating the Nrf2-PPARγ-sFlt-1 axis, suggesting a potential therapeutic target for preeclampsia.

Key Findings

• L-(+)-Ergothioneine (LET) increased viability and migration of LPS-induced trophoblasts and inhibited apoptosis.
• LET downregulated pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and endothelial dysfunction markers (sFlt-1, ET-1, PAI-1), while upregulating anti-inflammatory cytokine IL-4 and plasminogen activators (tPA, uPA).
• LET modulated the Nrf2-PPARγ-sFlt-1 axis by inhibiting Nrf2 nuclear translocation and promoting PPARγ expression, leading to reduced sFlt-1 levels and improved endothelial recovery.

Clinical Significance

Citation

Gong Jingjin, Liu Yan, Meng Qingjuet al.. L-(+)-Ergothioneine ameliorates preeclampsia-associated vascular endothelial dysfunction by modulating the Nrf2-PPARγ-sFlt-1 axis. PloS one. 2026.