biostudies-literatureBabolmorad GNatural Sciences and Engineering Research Council of CanadaAlberta Cancer FoundationKids With Cancer SocietyCanadian Institutes of Health ResearchCanada Research ChairsCIHRe51280https://www.ebi.ac.uk/biostudies/studies/S-EPMC8097357biostudies-literatureUnknown22(5)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 can be activated by the Group 10 metal platinum and the platinum-based chemotherapeutic cisplatin. Cisplatin is invaluable in childhood cancer treatment but its use is limited due to a permanent hearing loss (cisplatin-induced ototoxicity, CIO) adverse effect. We demonstrate that platinum and cisplatin activate pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. We further show that TLR4 is required for cisplatin-induced inflammatory, oxidative, and cell death responses in hair cells in vitro and for hair cell damage in vivo. Finally, we identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicity in vitro. Thus, our findings indicate that TLR4 is a promising therapeutic target to mitigate CIO.EMBO reportsToll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity.PMC809735727176MY2-1553612631RGPIN‐2019‐04825231622MY2‐155361Bhavsar APDomingo IKDelyea CRieger AMPollock NMBabolmorad GLatif AAllison WTfalseToll-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 can be activated by the Group 10 metal platinum and the platinum-based chemotherapeutic cisplatin. Cisplatin is invaluable in childhood cancer treatment but its use is limited due to a permanent hearing loss (cisplatin-induced ototoxicity, CIO) adverse effect. We demonstrate that platinum and cisplatin activate pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. We further show that TLR4 is required for cisplatin-induced inflammatory, oxidative, and cell death responses in hair cells in vitro and for hair cell damage in vivo. Finally, we identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicity in vitro. Thus, our findings indicate that TLR4 is a promising therapeutic target to mitigate CIO.2021-01-01T00:00:00Z2021 May2025-04-19T02:33:58.914Z2025-04-07T12:59:50.38ZS-EPMC80973573373357310.15252/embr.202051280