Abstract
A BSTRACT Male infertility is increasingly recognized as a systems-level disorder where dysregulated redox homeostasis intersects with innate immune activation. Affecting approximately one in six individuals during their reproductive lifetime, male infertility is defined by the failure to conceive after 12 months of regular, unprotected intercourse. Oxidative stress, characterized by an excess of reactive oxygen species (ROS) relative to antioxidant defenses, impairs sperm function through lipid peroxidation, mitochondrial dysfunction, and DNA damage, while concurrently amplifying inflammatory signaling. Major ROS sources include sperm mitochondria, seminal leukocytes, NADPH oxidases (notably sperm NOX5), and oxidase systems linked to defective spermiogenesis. ROS activate redox-sensitive pathways, such as nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), as well as NLRP3 inflammasome signaling, establishing feed-forward loops that disrupt spermatogenesis, steroidogenesis, and sperm quality. Human and animal studies demonstrate associations between elevated seminal cytokine levels (interleukin-6, tumor necrosis factor-alpha, CXCL8), NOX5 upregulation, excess ROS, and DNA damage, as well as testicular NLRP3 activation in infection and toxin models. Therapeutically, broad antioxidant supplementation remains controversial; large randomized trials have shown no benefit and potential harm in unselected men, while meta-analyses suggest possible benefits with low certainty and high bias. Future progress likely depends on endotype-based patient selection using oxidative and inflammatory biomarkers, the development of pathway-specific interventions targeting NOX, NF-κB/MAPK, and NLRP3/caspase-1, and the refinement of assisted reproductive technology laboratory strategies to minimize iatrogenic oxidative injury.