Yang Xi, Feng Qing
Department of Obstetrics and Gynecology, Third Xiangya Hospital of Central South University, Changsha, China.
Commun Biol. 2025 Jul 1;8(1):973. doi: 10.1038/s42003-025-08375-3.
Endometrial fibrosis is the main feature of intrauterine adhesion (IUA). The m6A methylation is involved in the process of fibrosis. However, the regulatory pathways involved in m6A methylation in endometrial fibrosis remain unclear. ALKBH5 is differentially low expressed in the endometrial tissues of IUA. Overexpression of ALKBH5 inhibits TGF-β1-induced fibrosis. In the in vivo experiment, ALKBH5 overexpression reduces the degree of endometrial fibrosis in rats. ALKBH5 regulates the m6A methylation level of FABP4 mRNA. FABP4 expression is inhibited by WT-ALKBH5, but not by catalytically inactive MUT-ALKBH5 (H204A). The m6A reader IGF2BP2 targets FABP4 and affects FABP4 mRNA stability. Inhibition of FABP4 decreases the expression of fibrosis-related markers (α-SMA, collagen I, collagen III, and Fibronectin). In addition, serum lipid metabolism is disordered in IUA rats, and ALKBH5 overexpression could partially reverse the levels of differential lipid metabolites. In conclusion, ALKBH5 is differentially low expressed in IUA. ALKBH5 signaling regulates endometrial fibrosis through FABP4 mRNA m6A methylation and lipid metabolism. This finding can provide theory support for the potential treatment strategy development of IUA.
子宫内膜纤维化是宫腔粘连（IUA）的主要特征。m6A甲基化参与纤维化过程。然而，子宫内膜纤维化中m6A甲基化所涉及的调控途径仍不清楚。ALKBH5在IUA的子宫内膜组织中差异低表达。ALKBH5的过表达抑制转化生长因子-β1诱导的纤维化。在体内实验中，ALKBH5过表达降低大鼠子宫内膜纤维化程度。ALKBH5调节FABP4 mRNA的m6A甲基化水平。FABP4的表达受到野生型ALKBH5的抑制，但不受催化失活的突变型ALKBH5（H204A）的抑制。m6A阅读蛋白IGF2BP2靶向FABP4并影响FABP4 mRNA稳定性。抑制FABP4可降低纤维化相关标志物（α-平滑肌肌动蛋白、I型胶原、III型胶原和纤连蛋白）的表达。此外，IUA大鼠的血清脂质代谢紊乱，ALKBH5过表达可部分逆转差异脂质代谢物的水平。总之，ALKBH5在IUA中差异低表达。ALKBH5信号通过FABP4 mRNA的m6A甲基化和脂质代谢调节子宫内膜纤维化。这一发现可为IUA潜在治疗策略的开发提供理论支持。
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