顺铂是一种常用的抗癌化合物，但其在非靶器官产生严重毒性。鉴于其在癌症治疗中的广泛应用，减少其对正常组织的损害已成为迫切的临床需求。顺铂引起的睾丸氧化应激和损伤导致男性生育能力下降或不育。虽然早期研究表明天然多酚提取物红杉酚作为自由基清除剂可以减少细胞内自由基的积累，但红杉酚对睾丸和精子的直接作用尚不清楚。因此，本研究的目的是研究红杉酚对睾丸恢复和精子生理的直接影响。 我们将这种多酚抗氧化化合物包装到基于脂质体的纳米颗粒（nHNK）中，并以每隔一天给予小鼠5 mg/kg体重的剂量，连续6周给药。我们发现，nHNK促进MDC1-53bp1相关的非同源DNA双链断裂修复信号途径，从而最小化顺铂引起的DNA损伤。这种积极作用恢复了精子发生，并允许睾丸多精子层的重构。通过减少线粒体氧化损伤，nHNK还保护了精子线粒体结构，并维持了睾丸和精子的ATP产生。通过尚未确定的机制，nHNK恢复了精子中段和尾部的钙离子入流，这对于精子的高活性和与卵子的相互作用至关重要。 综上所述，纳米颗粒抗氧化剂抵消了顺铂引起的男性生育缺陷，并使接受顺铂基化疗的患者受益。这些数据可能允许顺铂在临床中应用于具有减少睾丸毒性的患者。© 2023 Wei等。

Cisplatin, a commonly used anticancer compound, exhibits severe off-target organ toxicity. Due to its wide application in cancer treatment, the reduction of its damage to normal tissue is an imminent clinical need. Cisplatin-induced testicular oxidative stress and damage lead to male sub- or infertility. Despite earlier studies showing that the natural polyphenol extracts honokiol serve as the free radical scavenger that reduces the accumulation of intracellular free radicals, whether honokiol exhibits direct effects on the testis and sperm is unclear. Thus, the aim of the current study is to investigate the direct effects of honokiol on testicular recovery and sperm physiology.We encapsulated this polyphenol antioxidation compound into liposome-based nanoparticles (nHNK) and gave intraperitoneally to mice at a dosage of 5 mg/kg body mass every other day for consecutive 6 weeks.We showed that nHNK promotes MDC1-53bp1-associated non-homologous DNA double-strand break repair signaling pathway that minimizes cisplatin-induced DNA damage. This positive effect restores spermatogenesis and allows the restructuring of the multi-spermatogenic layers in the testis. By reducing mitochondrial oxidative damage, nHNK also protects sperm mitochondrial structure and maintains both testicular and sperm ATP production. By a yet-to-identify mechanism, nHNK restores sperm calcium influx at the sperm midpiece and tail, which is essential for sperm hypermotility and their interaction with the oocyte.Taken together, the nanoparticulated antioxidant counteracts cisplatin-induced male fertility defects and benefits patients undertaking cisplatin-based chemotherapy. These data may allow the reintroduction of cisplatin for systemic applications in patients at clinics with reduced testicular toxicity.© 2023 Wei et al.