Wang Ziwei, Mao Yanhong, Wang Zihan, Li Shuwei, Hong Zhidan, Zhou Rong, Xu Shaoyuan, Xiong Yao, Zhang Yuanzhen
Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.
Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei, People's Republic of China.
Am J Physiol Cell Physiol. 2025 Feb 1;328(2):C500-C513. doi: 10.1152/ajpcell.00493.2024. Epub 2024 Dec 13.
Histone lactylation is crucial in a variety of physiopathological processes; however, the function and mechanism of histone lactylation in endometriosis remain poorly understood. Therefore, the objective of this investigation was to illuminate the function and mechanism of histone lactylation in endometriosis. Immunohistochemistry was used to investigate the expression of histone lactylation. Cell Counting Kit-8 assay (CCK8), Transwell assay, and endometriosis mouse models were used to investigate the effects of histone lactylation in vitro and in vivo. Transcriptomics and immunoprecipitation-mass spectrometry (IP-MS), Western blot, co-immunoprecipitation (Co-IP), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to explore the intrinsic mechanisms. In this study, we found that histone lactylation was upregulated in endometriosis and could promote endometriosis progression both in vivo and in vitro. Mechanistically, histone lactylation H3K18la promoted the transcription of Ras homolog enriched in striatum (RASD2), and RASD2, in turn, increased the stability of CTP synthase 1 (CTPS1) by promoting the SUMOylation and inhibiting the ubiquitination of CTPS1, thereby promoting endometriosis progression. Overall, our findings indicated that histone lactylation could promote the progression of endometriosis through the RASD2/CTPS1 axis. This investigation uncovered a novel mechanism and identified prospective targets for endometriosis diagnosis and therapy. Our finding reveals a novel mechanism that promotes the progression of endometriosis, namely the histone lactylation/RASD2/CTPS1 axis. This finding suggests that inhibiting histone lactylation or inhibiting RASD2 and CTPS1 might be a potential therapeutic strategy to inhibit endometriosis lesion growth.
组蛋白乳酸化在多种生理病理过程中至关重要；然而，组蛋白乳酸化在子宫内膜异位症中的功能和机制仍知之甚少。因此，本研究的目的是阐明组蛋白乳酸化在子宫内膜异位症中的功能和机制。采用免疫组织化学法检测组蛋白乳酸化的表达。使用细胞计数试剂盒8法（CCK8）、Transwell实验和子宫内膜异位症小鼠模型来研究组蛋白乳酸化在体内和体外的作用。运用转录组学和免疫沉淀-质谱法（IP-MS）、蛋白质免疫印迹法、免疫共沉淀法（Co-IP）、定量逆转录聚合酶链反应（qRT-PCR）和染色质免疫沉淀-qPCR（ChIP-qPCR）来探究其内在机制。在本研究中，我们发现组蛋白乳酸化在子宫内膜异位症中上调，并且在体内和体外均可促进子宫内膜异位症进展。机制上，组蛋白乳酸化H3K18la促进富含纹状体的Ras同源物（RASD2）的转录，而RASD2反过来通过促进CTP合酶1（CTPS1）的SUMO化并抑制其泛素化来增加CTPS1的稳定性，从而促进子宫内膜异位症进展。总体而言，我们的研究结果表明组蛋白乳酸化可通过RASD2/CTPS1轴促进子宫内膜异位症进展。本研究揭示了一种新机制，并确定了子宫内膜异位症诊断和治疗的潜在靶点。我们的发现揭示了一种促进子宫内膜异位症进展的新机制，即组蛋白乳酸化/RASD2/CTPS1轴。这一发现表明抑制组蛋白乳酸化或抑制RASD2和CTPS1可能是抑制子宫内膜异位症病灶生长的潜在治疗策略。
