Proposed mechanism of cisplatin-induced cochlear inflammation

Following its entry into the cochlea and uptake by cells via either simple or facilitated diffusion, cisplatin induces an inflammatory response through various signaling pathways, including TLR4-NF-kappaB activation, TLR4-NF-κB-NLRP3 inflammasome activation, NOX3-NF-kappaB activation, NOX3-STAT1 activation, XO-NF-kappaB/STAT1 activation, reductions in antioxidant enzyme levels, STAT3 inhibition, and mast cell degranulation. The upregulation of proinflammatory mediators in the cochlea leads to the infiltration and activation of macrophages.

Abbreviations: COX-2, cyclooxygenase 2; CTR1, copper-like transporter-1; CXCL1, chemokine (C-X-C motif) ligand 1; IL-1β, interleukin-1β; IL-18, interleukin-18; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; NOX3, NADPH oxidase 3; OCT2, organic cation transporter-2; ROS, reactive oxygen species; STAT1, signal transducer and activator of transcription-1; STAT3, signal transducer and activator of transcription-3; TNF-α, tumor necrosis factor-alpha; TLR4, Toll-like receptor 4; TMC1, transmembrane channel-like protein 1; XO, xanthine oxidase.

(Source: Tan WJ, Vlajkovic SM. Molecular characteristics of cisplatin-induced ototoxicity and therapeutic interventions. Int J Mol Sci 2023;24[22]:16545. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)