Integrative genomic and multi-omics analyses identify oxidative stress-related pathways and druggable targets for...

Tinnitus is a complex auditory perceptual disorder often accompanied by neuroinflammatory responses and metabolic abnormalities. Increasing evidence suggests that persistent oxidative stress, together with its interactions with immune regulation and energy metabolism, contributes to the pathophysiology of tinnitus. However, the molecular mechanisms by which oxidative stress drives tinnitus development remain to be systematically elucidated.

We integrated GWAS meta-analysis with DNA methylation, gene expression, and protein QTLs for 1,844 oxidative stress-related genes. Candidate genes were prioritized via SMR and colocalization, then validated in independent cohorts and brain-specific datasets, and further experimentally confirmed by assessing protein and RNA levels in human peripheral blood plasma. To further investigate oxidative stress-related pathways, mediation analyses were conducted, while molecular docking explored druggability.

Based on integrated multi-omics evidence, ACADVL was identified as a primary candidate target for tinnitus. Beyond in silico analyses, compared with healthy controls, ACADVL mRNA expression and VLCAD protein levels were both increased in patients with tinnitus. ACADVL increased tinnitus risk by suppressing CD25 on IgD⁺CD38^- B cells (10%) and altering the phosphate-to-oleoyl-linoleoyl-glycerol ratio (8.5%), highlighting oxidative stress -mediated immune and metabolic pathways. Molecular docking confirmed fenretinide as a potential therapeutic agent.

This study provides convergent evidence from genetic, multi-omics, and experimental analyses that oxidative stress-related genes, particularly ACADVL, may increase susceptibility to tinnitus through metabolic and inflammatory dysregulation. Molecular docking and drug enrichment analyses further confirmed the druggability of these targets, highlighting fenretinide as a promising repurposable therapeutic candidate. By integrating genetic epidemiology, functional validation, and drug target identification based on molecular docking, this work establishes a framework for mechanistic investigation and therapeutic development in tinnitus.