Busulfan-Induced Male Infertility: Mechanisms, Therapeutic Interventions, and Future Directions

This review summarizes the molecular and cellular mechanisms underlying busulfan-induced male infertility and evaluates the translational potential of current and emerging therapeutic strategies. Evidence indicates that busulfan induces germ cell DNA alkylation damage, triggers sustained oxidative stress, and activates multiple cell death pathways. These events are accompanied by supporting cell dysfunction, disruption of the blood-testis barrier (BTB), and endocrine imbalance, collectively driving progressive impairment of spermatogenesis. In response to these pathological processes, various interventions have been explored, including antioxidant molecules, natural extracts, epigenetic modulation, and stem cell-related approaches, many of which show partial improvement of spermatogenic function in experimental models. In addition, clinical strategies used for other forms of male infertility, such as gonadotropin supplementation and antioxidant supportive therapy, provide relevant reference frameworks for chemotherapy-associated fertility impairment. However, most studies on busulfan-induced infertility remain preclinical, and their benefits largely reflect supportive modulation of the testicular microenvironment rather than definitive restoration of spermatogonial stem cells (SSCs) or repair of genotoxic damage. Based on an integrated assessment of current evidence, this review highlights key unresolved challenges, including the lack of a defined therapeutic safety window, limitations in targeted delivery, and difficulties in achieving fundamental reconstruction of the spermatogenic system. Accordingly, future studies should place greater emphasis on more effective isolation and protection of testicular tissue, development of targeted drug delivery systems, and strategies aimed at spermatogenic system reconstruction.