Recurrent implantation failure (RIF) remains a challenging clinical issue in assisted reproductive technologies, affecting approximately 10% of couples undergoing in vitro fertilization procedures. Despite these advancements, the precise molecular mechanisms underlying RIF, particularly in women under 35 years of age, remain poorly understood. This narrative review systematically analyzed contemporary literature from 2015 to 2025 to elucidate the genetic and epigenetic factors implicated in RIF, providing critical insights into the underlying pathophysiological mechanisms. A structured literature review was conducted using the PICOT framework, guiding searches across databases such as PubMed, ScienceDirect, Scopus, Google Scholar, ResearchGate, and Cochrane Library. The inclusion criteria prioritized robust original research, systematic reviews, and meta-analyses addressing genetic and epigenetic mechanisms, specifically in women under 35 years of age with RIF.Significant genetic polymorphisms were identified, notably within immune regulatory genes (HLA-G), apoptosis-related genes (FAS, FAS-L), and angiogenesis-associated genes (VEGFA, KDR), which critically influence endometrial receptivity and implantation. Additionally, substantial epigenetic dysregulation was noted, including aberrant DNA methylation patterns (HOXA10, LIF, and NLRP2) and histone modifications, such as hypoacetylation and increased H3K27 trimethylation. Dysregulated miRNA profiles, particularly elevated levels of let-7a, adversely affect key biological pathways, including cell adhesion, immune modulation, and angiogenesis. This review highlights the pivotal role of genetic-epigenetic interactions in shaping the endometrial environment conducive to implantation. Methodological discrepancies among studies and a lack of standardized diagnostic criteria were identified as limitations, emphasizing the need for longitudinal multi-omics research employing standardized protocols and diverse patient cohorts. Integrating these molecular insights into clinical diagnostics and therapeutic strategies promises enhanced precision and effectiveness in RIF management, ultimately improving reproductive medicine outcomes.
Μεμέτ Ι. Νιχάν (Wed,) studied this question.