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After entering the cochlea, cisplatin is taken up into cells by diffusive and passive transport, copper transporter protein 1 (Ctr1) and organic cation transporter protein 2 (OCT2), endocytosis, and toxicity through DNA adduct formation, oxidative stress, mitochondrial dysfunction, inflammatory response, and ferroptosis ( 2.1 Cisplatin-induced DNA damage and apoptosis Once cisplatin enters the cell it can be hydrolyzed to form toxic aqua-cisplatin complexes and form intra-and interstrand crosslinks with DNA (Figure 1) FIGURE 1 2.2 Cisplatin induces oxidative stress The cochleas high metabolic rate results in its production of abundant reactive oxygen species (ROS), so it requires an active antioxidant defense system [glutathione (GSH), oxidized glutathione (GSSG), and antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR)] to achieve a dynamic oxidant-antioxidant balance to maintain healthy hearing