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

Unexplained recurrent spontaneous abortion (URSA) 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. 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 (SASP) axis. Subsequently, this axis was validated both in vitro decidualization models and URSA murine models. 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. 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.