Monocarboxylate transporter 6 mediates sex-dependent cisplatin ototoxicity via metabolite uptake

Cisplatin is a widely used anticancer drug, but up to 75% of patients develop ototoxicity, for which there are no fully effective preventive or curative therapies. Although genetic variation in the monocarboxylate transporter 6 (MCT6; SLC16A5) has been associated with reduced cisplatin-induced hearing loss, these findings have not been consistently replicated, and the underlying mechanism has remained unclear. We hypothesized that MCT6 mediates uptake of a cytotoxic cisplatin metabolite and that loss of MCT6 confers protection from cisplatin-induced ototoxicity. Here we show that MCT6 selectively mediates uptake of the cisplatin metabolite N-acetyl-L-cysteine-cisplatin and drives sex-dependent ototoxicity in vivo. Using genetic, pharmacokinetic, and functional auditory approaches, we demonstrate that Mct6 deficiency does not alter systemic platinum exposure but provides robust protection from cisplatin-induced hearing loss in female, but not male, mice. Consistent with this phenotype, Mct6 expression is higher in female cochleae, and MCT6 overexpression increases cellular platinum accumulation following exposure to N-acetyl-L-cysteine-cisplatin but not cisplatin. Together, these findings identify MCT6 as a sex-dependent regulator of cisplatin ototoxicity through selective transport of a toxic platinum metabolite. SIGNIFICANCE STATEMENT: This study identifies MCT6 (SLC16A5) as a sex-dependent regulator of cisplatin ototoxicity by mediating cochlear transport of a toxic cisplatin metabolite, revealing a novel mechanism to reduce toxicity without altering systemic platinum exposure.