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PDHA1 Crotonylation Is Essential for Endometrial Metabolic Reprogramming and Decidualization in Normal Pregnancy

ABSTRACT: Endometrial decidualization is essential for pregnancy. Impaired decidualization is a hallmark of preeclampsia (PE), yet the underlying mechanisms remain unclear. Herewe show that uterine pyruvate dehydrogenase E1 subunit α (PDHA1) K385 crotonylation (K385cr) is crucial in metabolic reprogramming and decidualization. In PE women, decidual PDHA1 K385cr is markedly reduced. In mice, Pdha1 K385cr deficiency causes endometrial metabolic dysregulation, poor decidualization, and a PE-like phenotype. Mechanistically, crotonylation promotes PDHA1 phosphorylation, inhibiting pyruvate dehydrogenase activity and enhancing glycolysis and NAD+ generation. In turn, NAD+ increases SIRT2-mediated FOXO1 deacetylation and nuclear translocation, upregulating decidual gene expression. In Pdha1 K385cr deficient mice, treatment of the NAD⁺ precursor β-NMN enhances the NAD⁺-SIRT2 FOXO1 pathway and decidualization, alleviating the PE-like phenotype. Our results indicate that PDHA1 K385cr is a key metabolic regulator in the pregnant uterus and that impaired PDHA1 K385cr may contribute to PE, suggesting that enhancing the NAD⁺-SIRT2-FOXO1 pathway may be exploited for PE intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327790 | GEO | 2026/04/27

REPOSITORIES: GEO

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