噪声性听力损失 (NIHL) 是听力损伤的主要原因，但目前还没有 FDA 批准的药物可以预防这种情况。靶向丝裂原激活蛋白激酶 (MAPK) 细胞通路已成为减轻 NIHL 的一种有前景的方法。 Tizaterkib 是一种口服生物利用度高、特异性强的 ERK1/2 抑制剂，目前正处于 1 期抗癌临床试验中。在这里，我们测试了 tizaterkib 对小鼠永久性 NIHL 的功效，剂量相当于目前临床试验中人类处方的剂量。噪声暴露后 24 小时口服该药物，在雌性和雄性小鼠中，在三个频率上平均保护 20-25 dB SPL，治疗窗口 >50，并且没有为 KSR1 基因敲除小鼠提供额外的保护，显示药物通过 MAPK 途径发挥作用。 Tizaterkib 可以避免噪音引起的耳蜗突触病，并且为期 3 天、每天两次的药物治疗是最佳的确定方案。重要的是，tizaterkib 被证明可以减少噪声暴露后耳蜗中 CD45 和 CD68 阳性免疫细胞的数量，这可能是 MAPK 抑制的保护机制的一部分。

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor, currently in Phase-1 anticancer clinical trials. Here, we tested tizaterkib's efficacy against permanent NIHL in mice at doses equivalent to what humans are currently prescribed in clinical trials. The drug given orally 24 hours after noise exposure, protected an average of 20-25 dB SPL in three frequencies, in female and male mice, had a therapeutic window >50, and did not confer additional protection to KSR1 genetic knockout mice, showing the drug works through the MAPK pathway. Tizaterkib shielded from noise-induced cochlear synaptopathy, and a 3-day, twice daily, treatment with the drug was the optimal determined regimen. Importantly, tizaterkib was shown to decrease the number of CD45 and CD68 positive immune cells in the cochlea following noise exposure, which could be part of the protective mechanism of MAPK inhibition.