Oxidative Stress Pathways and Therapeutic Targets in Tinnitus via Multi-Omics
Overview
This study integrates genomic, epigenomic, transcriptomic, and proteomic data to identify oxidative stress-related genes implicated in tinnitus. ACADVL emerged as a key gene increasing tinnitus risk through immune and metabolic dysregulation, with fenretinide identified as a potential therapeutic agent.
Background
Tinnitus is a prevalent auditory disorder characterized by the perception of sound without external stimuli, often accompanied by neuroinflammation and metabolic abnormalities. Oxidative stress, resulting from an imbalance between reactive oxygen species and antioxidant defenses, plays a central role in cochlear damage and tinnitus pathophysiology. Genetic factors contribute to tinnitus susceptibility, but the molecular mechanisms remain poorly understood. Integrative multi-omics approaches can elucidate these mechanisms and identify novel therapeutic targets.
Data Highlights
Data Type
Findings
GWAS Meta-analysis
Identified oxidative stress-related genes associated with tinnitus
DNA Methylation, Gene Expression, Protein QTLs
Prioritized candidate genes via SMR and colocalization analyses
Experimental Validation
Increased ACADVL mRNA and VLCAD protein levels in tinnitus patients vs controls
Mediation Analysis
ACADVL influenced tinnitus risk by suppressing CD25 on IgD+CD38− B cells (10%) and altering phosphate-to-oleoyl-linoleoyl-glycerol ratio (8.5%)
Molecular Docking
Fenretinide identified as a promising drug candidate targeting ACADVL
Key Findings
ACADVL identified as a primary oxidative stress-related gene increasing tinnitus susceptibility.
Elevated ACADVL mRNA expression and VLCAD protein levels observed in tinnitus patients compared to healthy controls.
ACADVL modulates immune function by suppressing CD25 expression on IgD+CD38− B cells, contributing 10% to tinnitus risk.
Metabolic dysregulation via altered phosphate-to-oleoyl-linoleoyl-glycerol ratio accounts for 8.5% of tinnitus risk linked to ACADVL.
Molecular docking supports fenretinide as a potential repurposable therapeutic agent targeting oxidative stress pathways in tinnitus.
Integrated multi-omics and genetic epidemiology provide a robust framework for mechanistic and therapeutic exploration in tinnitus.
Clinical Implications
These findings highlight oxidative stress and its downstream immune and metabolic pathways as critical contributors to tinnitus pathophysiology. ACADVL represents a promising biomarker and therapeutic target, with fenretinide offering potential for drug repurposing. Clinicians should consider oxidative stress modulation strategies in managing tinnitus, moving beyond symptomatic treatment toward precision medicine approaches.
Conclusion
This comprehensive multi-omics study establishes oxidative stress-related gene ACADVL as a key driver of tinnitus through immune and metabolic dysregulation and identifies fenretinide as a candidate therapeutic agent. These insights pave the way for targeted interventions addressing the molecular basis of tinnitus.
Related Resources & Content
Comprehensive Genomic and Multi-Omics Approaches Reveal Oxidative Stress Pathways and Potential Therapeutic Targets for Tinnitus
