How a metabolic enzyme causes changes in gene packaging that trigger aging and reduced function in uterine support cells linked to recurrent miscarriage
HK2-driven glycolysis may promote stromal cell senescence and decidualization failure in through H3K18 lactylation, CUX1 activation, and factor transcription.
Evidence
The study used multi-omics profiling of primary stromal cells from URSA patients and controls, then tested the HK2-H3K18la-CUX1-SASP axis in vitro decidualization models and URSA mouse models.
Caveat
The evidence is mechanistic and model-based, so CUX1 remains a proposed therapeutic target rather than a clinically tested treatment for URSA.
Simplified
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.
Key numbers
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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