The SIRT1-p53 axis drives a ferro-aging-like program and aggravates trophoblast dysfunction in preeclampsia

Area of Science:

• Reproductive Biology
• Cellular Aging
• Biochemistry

Background:

• Preeclampsia (PE) is a pregnancy disorder linked to placental dysfunction.
• Premature placental senescence is implicated in PE pathogenesis, but upstream regulators are unclear.

Purpose of the Study:

• To investigate the role of SIRT1 in placental senescence and its link to iron dyshomeostasis in preeclampsia.
• To explore SIRT1 activation as a potential therapeutic strategy for PE.

Main Methods:

• Assessed placental SIRT1 expression in PE patients.
• Utilized trophoblast cell models with SIRT1 knockdown or pharmacological activation.
• Administered SIRT1 activators in vivo to induce PE-like symptoms.
• Investigated the interplay between iron homeostasis and senescence using iron chelators and senolytics.

Main Results:

• Reduced placental SIRT1 expression correlated with senescence in PE.
• SIRT1 knockdown in trophoblasts increased senescence, SASP release, and impaired cellular functions.
• SIRT1 activation attenuated placental senescence and ameliorated PE-like phenotypes in vivo.
• Iron dyshomeostasis and senescence exhibit a self-reinforcing interaction.

Conclusions:

• The SIRT1-p53 axis links iron dyshomeostasis to placental senescence in PE.
• A ferro-aging pathogenic program contributes to placental dysfunction in PE.
• Targeting the SIRT1 pathway offers potential therapeutic avenues for preeclampsia.