Redox homeostasis and therapeutic modulation: the central role of oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2) activation in systemic diseases and reproductive dysfunction.

Oxidative stress plays a critical role in the pathogenesis of various diseases. Oxygen-containing reactive molecules commonly called as reactive oxygen species (ROS), generated during the utilization of oxygen molecule by aerobic metabolism, often form the primary cause of oxidative stress. It leads to oxidative damage to lipids, proteins, and DNA, thus contributing to mitochondrial dysfunction, inflammation, and cell death. In systemic conditions such as neurodegenerative, cardiovascular, metabolic, and oncological disorders, ROS function both as signaling molecules and mediators of pathological processes. Central to the cellular defense against oxidative stress is the transcription factor called nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of antioxidant and cytoprotective genes. Activation of the Nrf2 pathway enhances redox homeostasis, detoxification, and cell survival, thereby offering significant therapeutic potential across diverse disease states. Particularly in the field of reproductive biology, ROS-induced damage to sperm DNA, membranes, and mitochondria impairs sperm function and viability, especially under pathological conditions and during sperm cryopreservation. Similarly, in female reproductive disorders, oxidative stress disrupts hormonal balance, follicular development, and implantation. Activation of Nrf2 through natural or synthetic compounds has shown promise in preserving sperm integrity, improving post-thaw outcomes, enhancing oocyte quality, and overall reproductive outcomes by augmenting antioxidant defense. The Nrf2 activators, such as flavonoid-based modulators, offer a protective mechanism by reducing oxidative injury and restoring reproductive homeostasis. Emerging evidence from both human and animal studies highlights the utility of flavonoids and Nrf2 activators in enhancing reproductive health, providing a foundation for novel antioxidant-based therapeutic interventions.