Advances in m6A Modification in Pregnancy-Related Disorders and Female Reproductive Endocrine Diseases

Female reproductive health depends on precisely coordinated molecular, endocrine, immune and metabolic regulation across the ovaries, endometrium, placenta, and early embryo (Ref. 1 ). Disruption of these processes contributes to a broad range of pregnancy-related disorders and endocrine diseases of the reproductive system, including recurrent implantation failure (RIF), preeclampsia (PE), miscarriage, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI), endometriosis and adenomyosis (Refs. 2 , 3 ). Although these conditions differ in clinical presentation and pathophysiological features, many involve abnormal gene regulation, altered cellular differentiation, inflammatory imbalance, metabolic dysfunction and defective tissue remodelling. Among the epigenetic and post-transcriptional mechanisms that regulate these processes, N6-methyladenosine (m6A) modification has attracted increasing attention (Refs. 4 , 5 ). m6A is the most prevalent internal modification of eukaryotic messenger RNA and is dynamically regulated by methyltransferases (‘writers’), demethylases (‘erasers’) and m6A-binding proteins (‘readers’) (Refs. 6 , 7 ). Through coordinated regulation of RNA splicing, export, translation, decay and stability, m6A influences cell fate decisions, developmental transitions, stress responses and tissue homeostasis (Refs. 6 , 8 ). An increasing number of studies suggest that abnormal m6A regulation contributes to diverse reproductive phenotypes, including impaired endometrial receptivity, trophoblast dysfunction, ovarian ageing, granulosa-cell injury, lesion invasion and endocrine-metabolic disturbance (Refs. 9 , 10 ). However, interpretation of the current literature remains challenging. Findings are often derived from a mixture of human clinical samples, animal models and cell-based experiments, and these different lines of evidence are not always clearly separated (Ref. 11 ). In addition, reported changes in the m6A regulators may vary depending on tissue source, cell type, disease stage, hormonal environment, hypoxic exposure, metabolic state and analytical platform (Refs. 11 , 12 ). As a result, the same regulator may appear protective in one biological context but pathogenic in another. This context dependence is a recurring theme across the field and is essential for interpreting apparently contradictory results. In this review, we summarize current evidence on the role of m6A modification in pregnancy-related disorders and female reproductive endocrine diseases, with particular emphasis on molecular mechanisms, biological context and major interpretive challenges. Rather than treating all reported associations as equivalent, we distinguish, where possible, between human, animal, and cell-based evidence; between causal and associative findings; and between broadly reproducible observations and more preliminary mechanistic reports. We also discuss major limitations and future priorities for this rapidly evolving field.

As the most prevalent internal RNA modification in eukaryotes, m6A has emerged as an important regulator in reproductive endocrinology. Increasing evidence suggests that the same m6A regulator may exert either protective or pathogenic effects depending on disease stage, cell type, hormonal context, and downstream targets. This context dependence remains a major challenge in the field. Several factors may contribute to this complexity. First, m6A regulators can influence diverse downstream transcripts and signaling pathways, leading to distinct biological outcomes in different cellular contexts. Second, female reproductive endocrine diseases are strongly influenced by hormonal fluctuations, which may reshape the epitranscriptomic landscape. Third, current detection technologies still face limitations in sensitivity, resolution, cost and reproducibility, thereby restricting cross-study comparisons and clinical translation. Future studies should therefore focus on several priorities: clarifying the downstream regulatory networks of m6A factors; analysing large-scale clinical samples to define disease-specific m6A signatures; applying emerging technologies such as single-cell sequencing, nanopore sequencing, CRISPR/Cas9-based functional screening, and advanced computational approaches; investigating the spatiotemporal dynamics of m6A during oocyte maturation, fertilization, and early embryogenesis; and exploring the crosstalk between m6A and other epigenetic mechanisms. Importantly, most, if not all, m6A writers, erasers, and readers have been reported to exhibit m6A-independent functions. These regulators may participate in gene expression control, protein–protein interactions, chromatin remodelling or signaling pathways independently of their roles in RNA methylation. Therefore, phenotypic effects observed in current studies cannot always be unequivocally attributed to m6A-dependent mechanisms, representing a potential confounding factor in the interpretation of existing literature. Future research should prioritize distinguishing m6A-dependent from m6A-independent effects through refined experimental strategies, such as catalytic-dead mutants, domain-specific functional analyses and integrative multi-omic approaches. Elucidating these non-canonical functions will not only improve mechanistic clarity but may also uncover novel pathways involved in reproductive disease pathogenesis, thereby expanding potential therapeutic targets beyond the m6A modification axis.

In summary, m6A RNA modification has emerged as a key epitranscriptomic regulator in pregnancy-related disorders and endocrine diseases of the female reproductive system, influencing trophoblast function, endometrial receptivity, ovarian biology and metabolic homeostasis. Current evidence consistently links dysregulated m6A machinery to disease phenotypes although most findings remain context dependent and are derived from a combination of human, animal, and cell-based studies. Importantly, the biological effects of individual m6A regulators vary across cell types, disease stages, and microenvironmental conditions, and may involve both m6A-dependent and m6A-independent mechanisms. Future studies integrating multi-omic approaches and well-defined clinical cohorts will be essential for clarifying causality and enabling the translation of m6A biological features into clinically relevant biomarkers and therapeutic strategies.