Copper, cuproptosis and male reproductive health: An updated and narrative review

Copper maintains a delicate equilibrium in male reproductive physiology serving as an important factor for mitochondrial enzymes while triggering severe cytotoxicity when homeostatic limits are exceeded. Copper-induced injury was previously associated with generalized redox imbalances and the identification of cuproptosis which is a distinct mode of regulated cell death introduces a novel framework for understanding its pathological effects. Recent animal and human studies indicate that copper overload disrupts the blood-testis barrier, suppresses the hypothalamic-pituitary-gonadal axis, and modifies the non-coding RNA landscape. Furthermore, bioinformatic analyses of human datasets have identified robust cuproptosis-related gene expressions demonstrating their potential as diagnostic biomarkers. Evaluating the transition from physiological copper signaling to cuproptotic cell death provides a rationale for targeted therapeutic interventions such as chelation therapy and the modulation of lipoylation pathways. Based on these new molecular advances and existing evidence, this review aims to comprehensively investigate copper metabolism and copper-mediated cell death pathways in the male reproductive system in detail.