Metabolomic and Cellular Mechanisms of Drug‐Induced Ototoxicity and Nephrotoxicity: Therapeutic Implications of Uric Acid Modulation

Certain medications, including cisplatin and neomycin, often cause both hearing loss and renal dysfunction. This study aims to uncover the common mechanisms behind drug-induced ototoxicity and nephrotoxicity to aid early diagnosis and treatment. Metabolomic analyses reveal simultaneous disruptions in endogenous metabolic networks in the kidney, inner ear, and serum after administrating cisplatin or neomycin. Notably, a marked elevation in uric acid (UA), a recognized indicator of renal tubular injury, is identified. Supplementing UA and inhibiting its renal excretion worsen hearing loss and hair cell damage. Single-cell nucleus sequencing and immunohistochemistry reveal major changes in xanthine oxidase and ABCG2, crucial for UA metabolism, primarily in cochlear stria vascularis cells rather than hair cells. Cisplatin triggers a significant release of UA from stria vascularis cells, reaching concentrations sufficient to induce autophagy-dependent ferroptosis in hair cells. In a coculture system, targeted interventions against these two proteins in stria vascularis cells, through either pharmacological inhibition or genetic manipulation, markedly decrease the elevated UA release and the subsequent ferroptosis of hair cells. These findings suggest a metabolic connection between the inner ear and the kidney, highlighting the therapeutic potential of modulating UA to mitigate drug-induced nephrotoxicity and ototoxicity.