What question did this study set out to answer?

The research aims to uncover the connection between apoptosis, pyroptosis, and inflammation in early-onset preeclampsia.

January 23, 2026Open Access

Caspase‐3/GSDME‐Mediated Trophoblast Pyroptosis and Reciprocal Macrophage Polarization Contribute to Inflammation in Early‐Onset Preeclampsia

Puntos clave

The research aims to uncover the connection between apoptosis, pyroptosis, and inflammation in early-onset preeclampsia.
Analyzed circulating pro-apoptotic proteins in early pregnancy of EOPE patients.
Performed experiments on multiple trophoblast cell lines to observe GSDME expression and pyroptosis.
Examined the effect of pyroptotic trophoblasts on macrophage polarization using trophoblast organoids-macrophage assembloids.
Conducted in vivo studies with wild-type and Gsdme −/− pregnant mice to test inflammation responses.
Screened potential EOPE prevention drugs, identifying Vitamin D's effect on pyroptosis.
Observed increased levels of pro-apoptotic proteins and CASP3 activation in EOPE placentas.
Demonstrated that trophoblast pyroptosis drives inflammatory responses through macrophage polarization.
Established a feedback loop enhancing both processes in organoid models.
Confirmed the role of CASP3-GSDME-mediated pyroptosis in systemic inflammation in wild-type, but not Gsdme −/− mice.
Identified Vitamin D as a potential suppressor for GSDME activation and pyroptosis.

Resumen

ABSTRACT Early‐onset preeclampsia (EOPE) is associated with excessive apoptosis and inflammation, but the mechanistic link between these processes remains enigma. Here, we report elevated circulating pro‐apoptotic proteins in EOPE patients at early pregnancy, along with concurrent CASP3 activation and GSDME cleavage in EOPE placentas. Using multiple trophoblast cell lines, we demonstrate that trophoblast cells, which highly express GSDME, undergo a shift from apoptosis to CASP3‐dependent pyroptosis, driving inflammation. Notably, pyroptotic trophoblasts further induce pro‐inflammatory macrophage polarization within placental villi organoids, establishing a feedback loop that amplifies both trophoblast pyroptosis and inflammatory responses in trophoblast organoids‐macrophage assembloids. In vivo, CASP3‐GSDME‐mediated trophoblast pyroptosis contributes to systemic inflammation in wild‐type pregnant mice but not in Gsdme −/− mice. Screening of EOPE prevention drugs reveals Vitamin D as a suppressor of GSDME activation and pyroptosis in trophoblast cells. Together, our findings establish CASP3–GSDME–mediated pyroptosis as a mechanistic link between apoptosis and inflammation in EOPE.

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