Mechanistic insights into the potential role of botanical drugs and plant-derived metabolites in mitigating oxidative stress in varicocele

Varicocele (VC) is a prevalent male urogenital disorder associated with scrotal discomfort, impaired semen quality, and endocrine dysregulation, in which oxidative stress (OS) is repeatedly implicated as a key pathogenic axis linking venous stasis, hypoxia, hyperthermia, inflammation, mitochondrial dysfunction, and germ-cell injury. This review critically evaluates experimental and clinical evidence on defined botanical drugs and plant-derived metabolites investigated in VC or VC-relevant OS models, with an emphasis on mechanistic plausibility and translational limitations. Across in vivo VC models, toxin-/heat-/hypoxia-induced spermatogenic injury models, and selected clinical studies, multiple interventions have been reported to improve semen parameters, testicular histology, and redox indices (e.g., ROS, MDA, SOD/CAT/GPx, GSH/GSSG), alongside modulation of apoptosis and stress responses. Reported molecular nodes converge on redox- and stress-responsive pathways, including Keap1–Nrf2–ARE/HO-1, PI3K–Akt, MAPK/JNK–p38, HIF-1–related signaling, ER-stress responses, mitochondrial apoptosis (e.g., Bax/Bcl-2/caspases), and, in some models, ferroptosis-related regulation. However, the overall evidence base is constrained by heterogeneity in models and endpoints, limited extract/compound chemical characterization and pharmacological standardization, frequent reliance on in silico predictions, small or non-randomized clinical cohorts, and incomplete reporting of taxonomic and product quality details. Future work should prioritize rigorously designed, adequately powered clinical trials with standardized outcomes, well-defined interventions, and mechanism-aligned biomarkers to clarify which botanical drugs/metabolites offer clinically meaningful benefit as adjuncts in VC management.