Toll‐like receptor 4 is activated by platinum and contributes to cisplatin‐induced ototoxicity

Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and can also be activated by some Group 9/10 transition metals, which is believed to mediate immune hypersensitivity reactions. In this work, we test whether TLR4 the 10 metal platinum platinum-based chemotherapeutic cisplatin. Cisplatin invaluable in childhood cancer treatment but its use limited due a permanent hearing loss (cisplatin-induced ototoxicity, CIO) adverse effect. We demonstrate that cisplatin activate pathways downstream of similar extent as known agonists LPS nickel. further show required for cisplatin-induced inflammatory, oxidative, cell death responses hair cells vitro damage vivo. Finally, identify small molecule inhibitor able curtail toxicity vitro. Thus, our findings indicate promising therapeutic target mitigate CIO.