HK2-driven histone H3K18 lactylation promotes stromal cell senescence and decidualization deficiency in URSA via CUX1-mediated SASP factor transcription

Mar 10, 2026Cellular & molecular biology letters

How a metabolic enzyme causes changes in gene packaging that trigger aging and reduced function in uterine support cells linked to recurrent miscarriage

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Abstract

Decidual tissues from patients with unexplained recurrent spontaneous abortion () showed evidence of stromal cell senescence and impaired decidualization.

HK2-driven glycolysis increased lactate production, leading to elevated histone lactylation at the CUX1 promoter.
CUX1 activation resulted in the transcription of factors associated with the senescence-associated secretory phenotype ().
Inhibition of glycolysis or depletion of CUX1 reversed the senescence and decidualization deficiencies in vitro.
CUX1 knockdown in a URSA murine model decreased stromal senescence and enhanced decidualization.
A novel signaling axis linking metabolic reprogramming to epigenetic regulation in URSA was identified.

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BACKGROUND: Unexplained recurrent spontaneous abortion () is characterized by defective endometrial stromal cell decidualization, with cellular senescence emerging as a key contributor. However, the metabolic-epigenetic mechanisms linking glycolysis to senescence-driven decidualization failure remain unclear. This study elucidates how hexokinase 2 (HK2)-mediated glycolytic reprogramming promotes histone lactylation-dependent stromal senescence and decidualization impairment in URSA.

METHODS: We employed multi-omics profiling (RNA-seq, metabolomics, and CUT&Tag) of primary stromal cells from patients with URSA and controls to map the histone H3K18 lactylation (H3K18la)-cut-like homeobox 1 (CUX1)-senescence-associated secretory phenotype () axis. Subsequently, this axis was validated both in vitro decidualization models and URSA murine models.

RESULTS: Decidual tissues from patients with URSA exhibited stromal cell senescence and impaired decidualization. Mechanistically, HK2-driven glycolysis elevated lactate production, which in turn promoted H3K18la at the CUX1 promoter. CUX1 then directly activated the transcription of key SASP factors, thereby propagating the senescence state. Critically, CUX1 depletion or glycolysis inhibition rescued these senescence and decidualization deficiency in vitro. Furthermore, CUX1 knockdown in the URSA murine model reduced stromal senescence and improved decidualization.

CONCLUSIONS: Our findings define a novel HK2-H3K18la-CUX1-SASP signaling axis that drives URSA pathogenesis by linking metabolic reprogramming with epigenetic regulation. This work highlights CUX1 as a potential therapeutic target for correcting decidualization deficiency in URSA.

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20 of 40

Participants

Cohort size includes 20 patients and 20 age-matched controls.

555

Lactate Levels

Global untargeted metabolomics revealed 555 differential metabolites in stromal cells.

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HK2-driven histone H3K18 lactylation promotes stromal cell senescence and decidualization deficiency in URSA via CUX1-mediated SASP factor transcription

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