MTHFD2: A metabolic checkpoint altering trophoblast invasion and migration by remodeling folate-nucleotide metabolism in recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) affects female reproduction worldwide, yet its pathological mechanisms are still unclear. It has been reported that cellular metabolism reprogramming is a critical step for trophoblasts during embryo implantation. Herein, MTHFD2 was recognized as a key metabolic checkpoint attributed to RSA occurrence. This work figured out that the expression level of MTHFD2 was significantly inhibited in villus tissues from RSA patients, suggesting the potential role of MTHFD2 in RSA occurrence. Moreover, MTHFD2 knockdown impaired cellular folate-nucleotide metabolism, induced the accumulation of AICAR, and thereby impairing the EMT process to inhibit the invasion and migration of trophoblasts Besides, the AICAR accumulation further activated the downstream AMPK which deactivated the JAK/STAT/Slug pathway and ultimately deactivated the EMT process. Using a mouse model, MTHFD2 inhibition was observed to induce embryo implantation failure in vivo. Our results highlighted MTHFD2 as a metabolic checkpoint that remodeled folate-nucleotide metabolism to regulate the EMT process and ultimately altered the migration and invasion of trophoblasts in RSA occurrence. Our findings suggested that MTHFD2 was a promising therapeutic target in recurrent spontaneous abortion treatment.