Downregulation of NNMT affects trophoblast function via inhibiting COMP/CD36/ERK1/2 axis in recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) is closely associated with trophoblast dysfunction, yet the underlying regulatory mechanisms remain poorly understood. Herein, we found a significantly decreased level of nicotinamide N-methyltransferase (NNMT) in RSA villous tissues compared to normal pregnancies. NNMT knockdown suppressed trophoblast proliferation, migration and invasion in vitro, and increased embryo absorption rate in vivo. Upstream of NNMT, FOXA1 was identified as its transcriptional regulator, which was also downregulated in RSA villous tissues. Mechanistically, reduced NNMT led to the accumulation of methyl donor S-adenosyl methionine, thus promoting the methylation of histone H3 at lysine 27. This epigenetic modification further inhibited the expression of cartilage oligomeric matrix protein (COMP), along with its binding to CD36 receptor and subsequent activation of ERK1/2 pathway in trophoblast. Together, our study demonstrates the crucial role of NNMT at the maternal-fetal interface, provides mechanistic insights into the pathogenesis of RSA, and lays a basis for developing targeted therapies.