Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss compared with their wild-type KSR1 littermates. KSR1 is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK1/2 and ERK1/2 and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. KSR1, BRAF, MEK1/2, and ERK1/2 are all ubiquitously expressed in the cochlea. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in male and female mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, protected male and female KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induced hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.

听力损失是日常生活中的主要残疾，保护听力的治疗干预措施将使世界大部分人口受益。在这里，我们发现，与野生型 KSR1 同窝小鼠相比，组织中缺乏 RAS 1 (KSR1) 蛋白激酶抑制因子的小鼠（种系 KO 小鼠）表现出对顺铂和噪音引起的永久性听力损失的抵抗力。 KSR1 是一种支架蛋白，可将丝裂原激活蛋白激酶 (MAPK) 蛋白 BRAF、MEK1/2 和 ERK1/2 带到附近，并通过顺铂和耳蜗细胞中的噪声损伤诱导的磷酸化级联来协助其激活。 KSR1、BRAF、MEK1/2 和 ERK1/2 在耳蜗中普遍表达。删除 KSR1 蛋白可以降低顺铂和噪音刺激后耳蜗细胞中的 MAPK 磷酸化级联，并在雄性和雌性小鼠的三个测试频率下提供高达 30 dB SPL 的听力保护。达拉非尼（FDA 批准的口服 BRAF 抑制剂）治疗可保护雄性和雌性 KSR1 野生型小鼠免受顺铂和噪音引起的听力损失。达拉非尼治疗并未增强对 KO KSR1 小鼠的保护作用，这提供了达拉非尼主要通过 MAPK 途径发挥作用的证据。因此，在小鼠中消除 KSR1 基因表达或药物抑制 MAPK 细胞通路可对顺铂和噪音引起的听力损失产生深远的保护。 MAPK 通路（一种对耳蜗细胞损伤做出反应的细胞通路）的抑制可以证明是保护和治疗听力损失的有价值的策略。