Histone Lactylation Promotes Endometriosis Progression by Upregulating CTPS1 SUMOylation

Academic Background

Endometriosis is a common reproductive endocrine disease affecting approximately 10% of women of reproductive age worldwide. Its main symptoms include dysmenorrhea, chronic pelvic pain, infertility, and menstrual abnormalities. Although the current primary treatments include medication and surgery, these methods often have limited efficacy, and endometriosis is prone to recurrence, significantly impacting patients’ quality of life and public health. Therefore, understanding the pathogenesis of endometriosis and exploring new targets for its early diagnosis and treatment have become important research directions.

Recent studies have shown that lactate, traditionally regarded as a metabolic waste product, also serves as a key substrate for histone lactylation, participating in the regulation of gene expression. Histone lactylation is a novel type of histone modification that affects chromatin accessibility by adding lactyl groups to lysine residues on histones, thereby regulating gene expression. Histone lactylation is closely related to various physiological and pathological processes, especially showing significant roles in tumorigenesis. However, despite similarities in biological behavior and genetic background between endometriosis and tumors, the role of histone lactylation in endometriosis remains unclear. Additionally, studies have found that serum lactate concentrations and lactate levels in endometrial stromal cells are significantly elevated in patients with endometriosis. Therefore, researchers hypothesized that elevated histone lactylation levels might promote the development of endometriosis.

Research Source

This paper was jointly completed by Ziwei Wang, Yanhong Mao, Zihan Wang, Shuwei Li, Zhidan Hong, Rong Zhou, Shaoyuan Xu, Yao Xiong, and Yuanzhen Zhang from the Reproductive Medicine Center of Zhongnan Hospital, Wuhan University. The paper was first published in the journal American Journal of Physiology-Cell Physiology on December 13, 2024, with the DOI: 10.1152/ajpcell.00493.2024.

Research Process and Results

1. Expression Profile of Histone Lactylation in Endometriosis

The study initially examined the expression levels of histone lactylation in normal endometrium (NC), eutopic endometrium (EU), and ectopic endometrium (EC) using immunohistochemistry. The results showed that H3K18la expression was significantly higher in EU and EC compared to NC during both the proliferative and secretory phases, indicating that H3K18la may play a crucial role in the progression of endometriosis.

2. Pro-endometriosis Effects of Histone Lactylation In Vitro

The researchers treated immortalized endometrial stromal cells (IESCs) with sodium lactate and glycolysis inhibitors (2-deoxy-D-glucose (2-DG) and sodium oxamate). They found that sodium lactate significantly upregulated histone lactylation levels, while 2-DG and sodium oxamate significantly downregulated them. Through cell proliferation, migration, and invasion assays, the researchers confirmed that histone lactylation promotes the proliferation, migration, and invasion capabilities of IESCs.

3. Screening for Target Genes of Histone Lactylation

Using RNA sequencing and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) experiments, the researchers discovered that H3K18la could promote the transcription of RASD2. RASD2 is a SUMO E3 ligase that exerts biological effects by regulating protein SUMOylation modifications. The study found that RASD2 expression was significantly upregulated after sodium lactate treatment, while it was significantly downregulated after 2-DG and sodium oxamate treatment.

4. RASD2 Enhances CTPS1 Stability by Promoting Its SUMOylation

Through immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) experiments, the researchers found that RASD2 interacts with CTPS1 and promotes its SUMOylation modification. CTPS1 is a key metabolic enzyme that catalyzes the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP), participating in cell proliferation and metabolism. The study found that RASD2 enhances the stability of CTPS1 by promoting its SUMOylation and inhibiting its ubiquitination, thereby promoting the progression of endometriosis.

5. Role of the Histone Lactylation/RASD2/CTPS1 Axis in Endometriosis

Through in vivo experiments, the researchers constructed an endometriosis mouse model and administered glycolysis inhibitors. The results showed that 2-DG and sodium oxamate significantly inhibited the growth of endometriosis lesions and reduced the expression levels of histone lactylation, RASD2, and CTPS1. These results indicate that inhibiting the histone lactylation/RASD2/CTPS1 axis can effectively suppress the progression of endometriosis.

Conclusions and Significance

This study revealed a new mechanism by which histone lactylation promotes the progression of endometriosis by upregulating RASD2 expression, enhancing CTPS1 SUMOylation, and increasing CTPS1 stability. This discovery provides new potential targets for the diagnosis and treatment of endometriosis. Inhibiting histone lactylation or targeting RASD2 and CTPS1 may become an effective therapeutic strategy to inhibit the growth of endometriosis lesions.

Research Highlights

1. Discovery of a New Mechanism: This study is the first to reveal the role of the histone lactylation/RASD2/CTPS1 axis in endometriosis, providing a new perspective for understanding the pathogenesis of this disease.
2. Potential Therapeutic Targets: RASD2 and CTPS1, as key regulators of endometriosis, may become new therapeutic targets in the future.
3. Combination of In Vivo and In Vitro Experiments: The study comprehensively validated the pro-progression role of histone lactylation in endometriosis through both in vivo and in vitro experiments, enhancing the credibility of the conclusions.

Other Valuable Information

The study also found that RASD2 can affect the stability of CTPS1 by regulating its SUMOylation and ubiquitination modifications, providing new insights into the role of protein modifications in diseases. Additionally, the potential application of glycolysis inhibitors in suppressing the progression of endometriosis offers experimental evidence for the future development of new therapeutic drugs.