The molecular puzzle of recurrent implantation failure: integrating genetic, epigenetic, and immune mechanisms for precision reproductive medicine.

Recurrent implantation failure (RIF) is a frustrating condition for the majority of infertile couples, occurring when pregnancy does not happen after several embryo transfers through assisted reproductive technologies (ART). ART has progressed over the last few years, but RIF continues for many patients, and the real reason remains unknown in most cases. RIF is a multifactorial condition influenced by both genetic and epigenetic mechanisms. Genetic contributions to RIF can be broadly classified into embryo-related factors (such as chromosomal aneuploidies and single-gene mutations), maternal factors (including mutations in uterine receptivity genes and immune-related polymorphisms), and paternal factors (notably sperm DNA fragmentation and chromosomal abnormalities). In addition, maternal epigenetic modifications-particularly aberrant DNA methylation, histone alterations, and dysregulation of non-coding RNAs-along with environmental and lifestyle influences, play a critical role in modulating gene expression essential for endometrial receptivity and successful embryo implantation. This review highlights recent scientific advancements in understanding how genetic and epigenetic factors influence the implantation process. It additionally investigates their capability as biomarkers for diagnosis and as targets for novel therapeutic strategies. Comprehending these molecular mechanisms could aid in creating tailored fertility therapies and enhancing success rates for couples experiencing RIF.