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

Area of Science:

• Ototoxicology
• Nephrotoxicology
• Metabolomics
• Molecular Biology

Background:

• Certain medications like cisplatin and neomycin can cause both hearing loss (ototoxicity) and kidney dysfunction (nephrotoxicity).
• The underlying shared mechanisms for these adverse drug effects remain incompletely understood, hindering effective early diagnosis and treatment strategies.

Purpose of the Study:

• To investigate the common molecular and metabolic pathways underlying drug-induced ototoxicity and nephrotoxicity.
• To identify potential therapeutic targets for mitigating these drug-induced toxicities.

Main Methods:

• Metabolomic analysis of kidney, inner ear, and serum following cisplatin or neomycin administration.
• Single-cell nucleus sequencing and immunohistochemistry to examine protein expression in cochlear cells.
• In vitro coculture systems to test targeted interventions.

Main Results:

• Metabolomic analysis revealed concurrent disruptions in metabolic networks in the kidney, inner ear, and serum.
• Elevated uric acid (UA) levels were identified as a key indicator of renal tubular injury, correlating with hearing loss and hair cell damage.
• Changes in xanthine oxidase and ABCG2, proteins involved in UA metabolism, were observed in cochlear stria vascularis cells.
• Cisplatin induced UA release from stria vascularis cells, leading to autophagy-dependent ferroptosis in hair cells.
• Inhibition of xanthine oxidase or ABCG2 in stria vascularis cells reduced UA release and hair cell ferroptosis.

Conclusions:

• A significant metabolic link exists between the inner ear and kidney in the context of drug toxicity.
• Modulating uric acid metabolism, particularly targeting xanthine oxidase and ABCG2 in the stria vascularis, presents a promising therapeutic strategy to prevent drug-induced ototoxicity and nephrotoxicity.