The role of sirtuins & NRF2 in reducing meiotic and mitotic errors in female fertility: Molecular mechanism & therapeutic potential

Reproductive potential varies globally, with fertility being a key determinant in the ability of millions to conceive, with errors in meiotic and mitotic processes during gametogenesis being one of the leading causes of reduced reproductive success. In assisted reproductive technologies (ART), such as in vitro fertilization (IVF) and intra cytoplasmic sperm injection (ICSI), genomic instability arising from chromosomal missegregation and spindle defects can lead to poor embryo quality, implantation failure, and miscarriage. Recent advances in molecular biology have highlighted the protective roles of sirtuins (SIRT1-SIRT7) and nuclear factor erythroid 2-related factor 2 (NRF2) in preserving cellular homeostasis, reducing oxidative stress, and promoting accurate chromosomal segregation during both meiosis and mitosis. Sirtuins are NAD⁺-dependent deacetylases that regulate a broad range of cellular processes including DNA repair, mitochondrial function, and the cell cycle, while NRF2 functions as a master regulator of antioxidant defense and redox balance. This review critically evaluates the molecular mechanisms by which sirtuins and NRF2 mitigate chromosomal errors in gametes and early embryos, and their implications in enhancing the outcomes of fertility treatments. We explore emerging evidence from animal models and human studies, discuss potential therapeutic interventions and pharmacological activators and highlight clinical applications and future directions. Understanding the roles of these regulatory proteins could pave the way for targeted therapies aimed at improving gamete quality and reproductive success.