Yang Guojun, Hu Na, Gao Jie, Li Xinzhi, Zhang Bin, Ma Ketao
Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Otolaryngology, The First Affiliated Hospital of Shihezi University, Shihezi 832000, China.
Antioxidants (Basel). 2025 May 22;14(6):619. doi: 10.3390/antiox14060619.
Cisplatin (Cis) is a commonly used chemotherapeutic agent for the clinical management of malignant tumors, but its toxic side effects could cause hearing loss, and there is an urgent need to find drugs that ameliorate Cis ototoxicity. Previous studies have found that ferulic acid (FA), a phenolic compound derived from natural plants, exerts antioxidant and anti-inflammatory effects by scavenging free radicals, preventing lipid peroxidation and cell death. Combination therapy, the use of multiple drugs to improve clinical outcomes, has multiple advantages compared to monotherapy. Another small-molecule ascorbic acid (AA) shows robust antioxidant function. However, the optimal route of administration, dosage, concentration, and effective time must be determined. More importantly, whether the combination of FA and AA can improve Cis ototoxicity and reduce the risk of large doses of AA is unclear. This study aims to evaluate the therapeutic potential of FA combined with AA in Cis-induced hearing impairment. In vitro and in vivo experiments were performed to observe the effects of FA, AA, and FA+AA on Cis-induced apoptosis. Compared with the Cis-only group, FA combined with AA ameliorated the Cis-induced decrease in cell viability, production of reactive oxygen species (ROS), and apoptosis of cells to varying degrees, respectively, and the improvement in cell viability, ROS, and apoptosis was even more pronounced with the combination of the two treatments. Network pharmacology combined with transcriptomics and molecular docking results showed that FA and AA could inhibit the Cis-induced apoptosis of cochlear hair cells through Matrix Metalloproteinase 9(MMP9)via the p38 Mitogen-Activated Protein Kinase (p38 MAPK) signaling pathway. In this study, we discovered that FA+AA reduced Cis ototoxicity by suppressing MMP9 in the MAPK signaling pathway.
顺铂（Cis）是临床上常用于治疗恶性肿瘤的化疗药物，但其毒副作用可导致听力丧失，因此迫切需要找到能改善顺铂耳毒性的药物。以往研究发现，阿魏酸（FA）是一种源自天然植物的酚类化合物，可通过清除自由基、防止脂质过氧化和细胞死亡发挥抗氧化和抗炎作用。联合治疗，即使用多种药物改善临床疗效，与单一疗法相比具有多种优势。另一种小分子抗坏血酸（AA）具有强大的抗氧化功能。然而，必须确定最佳给药途径、剂量、浓度和有效时间。更重要的是，FA和AA联合使用是否能改善顺铂耳毒性并降低大剂量AA的风险尚不清楚。本研究旨在评估FA联合AA对顺铂所致听力损伤的治疗潜力。进行了体外和体内实验，以观察FA、AA和FA+AA对顺铂诱导的细胞凋亡的影响。与单纯顺铂组相比，FA联合AA分别在不同程度上改善了顺铂诱导的细胞活力下降、活性氧（ROS）生成及细胞凋亡，且两种治疗联合使用时，细胞活力、ROS和细胞凋亡的改善更为明显。网络药理学结合转录组学和分子对接结果表明，FA和AA可通过基质金属蛋白酶9（MMP9）经由p38丝裂原活化蛋白激酶（p38 MAPK）信号通路抑制顺铂诱导的耳蜗毛细胞凋亡。在本研究中，我们发现FA+AA通过抑制MAPK信号通路中的MMP9降低了顺铂耳毒性。
