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

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

  • Cell Mol Biol Lett. 2026 Mar 9;31(1):31. doi: 10.1186/s11658-026-00879-y.
Xiaoxuan Zhao 1 2,  Yang Zhao 3,  Yuepeng Jiang 4,  Yiming Ma 5,  Jing Ma 1,  Hongli Zhao 6,  Xiaoling Feng 7
Affiliations

Affiliations

  • 1 Department of Traditional Chinese Medicine (TCM) Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China.
  • 2 Research Institute of Women's Reproductive Health Zhejiang Chinese Medical University, Hangzhou, 310007, China.
  • 3 The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
  • 4 Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 5 Macau University of Science and Technology, Macau, 999078, China.
  • 6 Department of Traditional Chinese Medicine (TCM) Gynecology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China. [email protected].
  • 7 Department of Gynecology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, China. [email protected].
PMID: 41803676 DOI: 10.1186/s11658-026-00879-y
Abstract

Background: 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.

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 (SASP) 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.

Keywords

CUX1; Cell senescence; Decidualization deficiency; Histone lactylation; SASP; Unexplained recurrent spontaneous abortion.

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