N6-methyladenosine epitranscriptomic alterations and their potential implications for maternal–fetal immune tolerance in obstetric antiphospholipid syndrome

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPL), such as anticardiolipin and anti-β2-glycoprotein I antibodies, in women experiencing obstetric complications. While vascular thrombotic events were considered the primary pathogenic mechanism in recent years, evidence indicates that the maternal-fetal interface in OAPS is altered by other underlying pathways, such as direct impairment of trophoblast invasion, dysregulation of immune cell activation, and platelet complement activation. These pathways act synergistically to compromise the immunological tolerance essential for fetal development. In parallel, recent research has highlighted the role of epigenetic modifications that maintain placental homeostasis and trophoblast proliferation. N6-methyladenosine (m6A) is the most abundant messenger RNA (mRNA) modification in mammals and plays a fundamental role in the maternal-fetal interface and the generation of immune tolerance. Specifically, the upregulation of m6A-modulating proteins is associated with recurrent pregnancy loss, defective placental artery remodeling, and HLA-G expression, a key factor in fetomaternal tolerance. Despite this knowledge, to date, no review has integrated m6A modification as a key mediator in the loss of immune tolerance in the context of adverse obstetric outcomes, including fetal growth restriction (FGR). In this review, we proposing a hypothetical model in which aPL exposure could induce alterations in the m6A methylation pattern that may affect the HLA-G/regulatory T cells (Treg)/uterine NK cells (uNK) axis potentially contributing to fetal loss, operating independently or in conjunction with prothrombotic mechanisms.