Semen Cuscutae-Fructus Lycii attenuates tripterygium glycosides-induced spermatogenesis dysfunction by inhibiting oxidative stress-mediated ferroptosis via the Nrf2/HO-1 pathway

Background: Semen Cuscutae and Fructus Lycii (SC-FL) is known for its potential therapeutic effects on spermatogenesis dysfunction. However, the underlying mechanisms of SC-FL in alleviating spermatogenesis dysfunction is still being elucidated. Purpose: This study aimed to explore the effects of SC-FL on spermatogenesis dysfunction and investigate the involved mechanisms, specifically focusing on the modulation of oxidative stress and ferroptosis. Methods: A mouse model of spermatogenesis dysfunction was induced by tripterygium glycosides, followed by treatment with SC-FL. Assessment of testicular spermatogenic function in the mice was performed alongside lipidomics analysis to investigate the metabolic mechanisms of SC-FL. The effects on oxidative stress and ferroptosis-related markers were evaluated, the chemical constituents of SC-FL were identified using liquid chromatography-mass spectrometry, and network pharmacology analysis was carried out. Additionally, an in vitro model of spermatogenesis dysfunction was established using triptolide-induced GC-1 cells, which were treated with Lycium barbarum polysaccharides (LBP) and flavonoids from Semen Cuscutae (FSC) to explore their impact on cell damage, oxidative stress-mediated damage, and ferroptosis. Results: SC-FL improved the mouse model of spermatogenesis dysfunction by inhibiting oxidative stress-mediated ferroptosis. In vitro experiments demonstrated that LBP and FSC relieved GC-1 cell damage, with their mechanisms also associated with the inhibition of oxidative stress-mediated ferroptosis. Conclusion: SC-FL alleviates spermatogenesis dysfunction in animal and cell models, potentially through the modulation of the Nrf2/HO-1 signaling pathway, which consequently inhibits oxidative stress-mediated ferroptosis in spermatogonial cells.