Decoding Recurrent Spontaneous Abortion through Multi-Level Regulation: The Emerging Roles of SETDB1

Recurrent spontaneous abortion (RSA) is a multifactorial reproductive disorder characterised by repeated pregnancy loss before foetal viability, and a substantial proportion of cases remain unexplained despite detailed clinical evaluation. Emerging evidence suggests that epigenetic dysregulation contributes to early pregnancy failure by influencing gene expression, immune balance and placental development. SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), a key mediator of histone H3 lysine 9 trimethylation (H3K9me3), has been implicated in transcriptional repression, genome stability and developmental regulation during early embryogenesis and placentation. This narrative review summarises current knowledge on the molecular structure and biological functions of SETDB1, with emphasis on its potential roles in reproductive biology and maternal–foetal immune tolerance. Experimental evidence indicates that SETDB1-dependent silencing of transposable elements, maintenance of imprinting integrity and regulation of lineage-specific gene expression are involved in oocyte maturation, preimplantation development, trophoblast differentiation and placental function. Potential mechanisms linking SETDB1 dysregulation to RSA include endogenous retrovirus activation, inflammatory signalling, impaired trophoblast–decidual interactions and disruption of immune homeostasis at the maternal–foetal interface. However, direct clinical evidence supporting a role for SETDB1 in human RSA remains limited, and most insights are derived from experimental and multi-omic studies. Accordingly, SETDB1 should be considered a biologically plausible epigenetic regulator rather than a confirmed driver of pregnancy loss. While its potential diagnostic or prognostic relevance has been proposed, such applications remain speculative. Further studies integrating clinical and functional data will be necessary to clarify the role of SETDB1 in RSA and its relevance within broader epigenetic frameworks in reproductive medicine.