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  3. Metabolomic and Cellular Mechanisms of Drug-Induced Ototoxicity and Nephrotoxicity: Therapeutic Implications of Uric Acid Modulation

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

  • Adv Sci (Weinh). 2025 Mar 5:e2415041. doi: 10.1002/advs.202415041.
Suhan Guo 1,  Cheng Cheng 2 3,  Yunhao Wu 4 5,  Kaidi Shen 1,  Depeng Zhang 1,  Bin Chen 1,  Xinyu Wang 1 6,  Luping Shen 1,  Qixiang Zhang 1,  Renjie Chai 3 5,  Guangji Wang 1,  Fang Zhou 1
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210096, China.
  • 3 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
  • 4 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
  • 5 State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
  • 6 Department of Pharmacy, General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
PMID: 40041973 DOI: 10.1002/advs.202415041
Abstract

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.

Keywords

autophagy‐dependent ferroptosis; cisplatin; hearing loss; nephrotoxicity; stria vascularis; uric acid.

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