中药复方AC591通过抑制p53介导的铁死亡保护顺铂诱导的听力损失

文献信息

中文摘要

顺铂是一种广泛用于治疗恶性肿瘤的化疗药物。然而，其严重的耳毒性显著限制了临床应用。因此，寻找保护性药物以预防顺铂诱导的听力损失（CIHL）至关重要。在此，我们发现源自经典方剂“黄芪桂枝五物汤”的AC591对顺铂诱导的耳毒性具有显著的保护作用。我们的研究结果表明，AC591预处理可减轻顺铂诱导的听觉功能障碍，其作用机制与抑制p53介导的铁死亡有关。通过鉴定口服给药后血清和耳蜗组织中AC591的活性成分，我们确认18β-甘草次酸是一种有效的听力保护成分。此外，我们证实18β-甘草次酸通过与p53结合并调节与铁死亡相关的蛋白发挥耳保护作用。总之，我们的研究结果表明，AC591和18β-甘草次酸可能作为预防CIHL的有前景的药物。

英文摘要

Cisplatin is a widely utilized chemotherapeutic agent for the treatment of malignant cancers. However, its clinical application is significantly restricted due to its severe ototoxicity. Therefore, identifying protective medications to prevent cisplatin-induced hearing loss (CIHL) is of paramount importance. Here, we show that AC591, derived from the classical herbal formula "Huangqi Guizhi Wuwu decoction," exhibits notable protective effects on cisplatin-induced ototoxicity. Our findings indicate that pretreatment with AC591 mitigates cisplatin-induced auditory dysfunction, with its mechanism of action linked to the inhibition of p53-mediated ferroptosis. By identifying the active components of AC591 in serum and cochlear tissues following oral administration, we recognized 18β-glycyrrhetinic acid as an effective constituent for hearing protection. Furthermore, we confirmed that 18β-glycyrrhetinic acid exerted otoprotective effects by binding to p53 and regulating proteins associated with ferroptosis. Collectively, our findings suggest that AC591 and 18β-glycyrrhetinic acid may serve as promising agents for preventing CIHL.