Liu Jun-Jun, Fang Yu-Qing, Xiong Wen-Qian, Liu Heng-Wei, Li Jing-Yi, Wang Xiu-Ping, Wang Hua-Jing, Zhang Ling, Liu Yi
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Wuhan Fourth Hospital, Wuhan, Hubei, China.
FASEB J. 2025 Jul 15;39(13):e70813. doi: 10.1096/fj.202500614R.
Endometriosis is a common gynecological endocrine disease with unclear pathogenesis. Evidence suggests enhanced aerobic glycolysis in ectopic endometrium of endometriosis. The role of N6-methyladenosine (m6A) modification in female reproductive diseases has been revealed in recent years, and it is involved in the regulation of glycolysis in a variety of diseases. Here, we investigated the regulatory effect of m6A modification on glycolysis and its role in endometriosis. RNA sequencing of ectopic endometrium of endometriosis and normal endometrium revealed that hexokinase 2 (HK2) a glycolysis-related gene, was significantly up-regulated in ectopic endometrium of endometriosis. Meanwhile, this result was supported by immunohistochemistry. Subsequently, we found that AlkB homolog 5 (ALKBH5) could upregulate HK2 in human endometrial stromal cells (THESCs). Up-regulation of ALKBH5 promoted glycolysis, invasion, and migration of THESCs, which could be alleviated by 2-Deoxy-d-glucose (2-DG). Furthermore, knockdown of HK2 in THESCs overexpressing ALKBH5 significantly attenuated the promoting effects of ALKBH5 on glycolysis, migration, and invasion of THESCs. Moreover, an ALKBH5 inhibitor, 5-Carboxy-8-hydroxyquinoline (IOX1) was found to inhibit the progression of endometriosis and glycolysis in a mouse model of endometriosis. In conclusion, ALKBH5 promoted glycolysis by up-regulating HK2 and contributed to the progression of endometriosis. ALKBH5 may be a new target for the treatment of endometriosis.
子宫内膜异位症是一种常见的妇科内分泌疾病，其发病机制尚不清楚。有证据表明，子宫内膜异位症异位内膜中的有氧糖酵解增强。近年来，N6-甲基腺苷（m6A）修饰在女性生殖疾病中的作用已被揭示，并且它参与多种疾病中糖酵解的调节。在此，我们研究了m6A修饰对糖酵解的调节作用及其在子宫内膜异位症中的作用。对子宫内膜异位症异位内膜和正常内膜进行RNA测序发现，糖酵解相关基因己糖激酶2（HK2）在子宫内膜异位症异位内膜中显著上调。同时，免疫组织化学也支持这一结果。随后，我们发现alkB同源物5（ALKBH5）可上调人子宫内膜基质细胞（THESC）中的HK2。ALKBH5的上调促进了THESC的糖酵解、侵袭和迁移，而2-脱氧-D-葡萄糖（2-DG）可缓解这种促进作用。此外，在过表达ALKBH5的THESC中敲低HK2可显著减弱ALKBH5对THESC糖酵解、迁移和侵袭的促进作用。此外，还发现一种ALKBH5抑制剂5-羧基-8-羟基喹啉（IOX1）在子宫内膜异位症小鼠模型中可抑制子宫内膜异位症的进展和糖酵解。总之，ALKBH5通过上调HK2促进糖酵解，并促进子宫内膜异位症的进展。ALKBH5可能是治疗子宫内膜异位症的新靶点。
