ALKBH5 regulates intrauterine adhesion progression through m6A dependent FABP4 mRNA stabilization and serum lipid metabolism.

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.