Limited studies have examined the association between DNA methylation age acceleration (DNAm AA) and hearing loss (HL). We aimed to assess whether plasma metabolite alterations are associated with the DNAm AA-HL association and explore the potential modifying effect of polygenic risk score (PRS). A total of 2,068 individuals aged 65.7 years from the Dongfeng-Tongji cohort in 2013 were included. Hearing threshold was assessed using pure tone average (PTA), and HL was defined as PTA >25 dB. DNAm AA was calculated using 6 epigenetic clocks (HorvathAge, HannumAge, PhenoAge, GrimAge, DunedinPACE and DNAm mortality risk score). Two hundred and ten plasma metabolites were profiled by targeted metabolomics approaches. We applied generalized linear model coupled with enrichment analysis to characterize metabolomic profiles of DNAm AA, and elastic-net regression to construct metabolomic risk score (MRS). A weighted PRS for HL was constructed using 37 single nucleotide polymorphisms. Among 2,068 participants, 1,075 (52.0%) had HL and exhibited significantly higher DNAm levels. HorvathAgeAccel, GrimAgeAccel, and DunedinPACE were associated with poorer PTA thresholds (β range: 0.59-1.56) and greater HL risks (odds ratios range: 1.11-1.21). GrimAgeAccel was linked to 28 metabolites and DunedinPACE to 65, involving 11 enrichment pathways and 6 metabolite sets. The MRSs were positively associated with PTA level or speech- and high-frequency HL (SFHL and HFHL) risk, and explained 33.4% to 48.2% of the associations of GrimAgeAccel and DunedinPACE with PTA or SFHL. Additionally, GrimAgeAccel and DunedinPACE exhibited positive associations with PTA or HL only in the high-PRS subgroup, and significant interaction was found between MRS for DunedinPACE and PRS on the risk of HFHL. GrimAgeAccel and DunedinPACE were associated with poorer PTA thresholds and higher HL risks, with their linked MRS partially explaining these associations. PRS modified the MRS-HFHL risk association, with a potentially amplified effect in high genetic susceptibility subgroups.

Hereditary deafness represents a significant global health challenge with limited therapeutic interventions. Most cases are caused by monogenic mutations inherited in an autosomal dominant or recessive manner, making them suitable targets for gene editing therapies. Recent advances in gene editing technologies have expanded the toolkit for precise genomic modification, including engineered nucleases for gene disruption, base editors (BEs) for point mutations, prime editors (PEs) for substitutions, insertions, and deletions, and mitochondrial editors for modifying mitochondrial DNA (mtDNA). These tools have demonstrated significant efficacy in mouse models of hereditary deafness, highlighting their clinical potential. However, given the high degree of genetic heterogeneity, gene editing technologies in this field remain in an early exploratory stage. In this review, we provide a comprehensive overview of the latest breakthroughs in gene-editing platforms and critically evaluate the potential benefits and existing hurdles to their clinical application for treating congenital hearing impairment.

Aminoglycoside (AG) antibiotics are indispensable for treating severe infections but frequently cause irreversible hearing loss, with no approved preventive therapies. Using in vivo zebrafish lateral line screening combined with computational scaffold-hopping, we identified a novel class of otoprotective compounds. Starting from the ion channel modulator MR16728, we discovered compound 28510 as a potent lead compound. Compound 28510 provided robust, dose-dependent protection against AG-induced hair cell damage, restoring neuromast hair cell integrity to near-control levels in acute assays and demonstrating broad efficacy across clinically relevant AGs (gentamicin, tobramycin, amikacin, streptomycin) in chronic exposures. Importantly, 28510 exhibited a favorable therapeutic window, with low micromolar 50% hair cell protection concentration (HC 50) values consistently below toxicity thresholds. Mechanistically, FM1-43 and Texas Red-conjugated gentamicin uptake assays revealed that 28510 does not inhibit mechanotransduction (MET) channel-mediated AG entry, distinguishing it from current clinical candidates and pointing to a novel intracellular protective mechanism. 28510 preserved AG antibacterial activity in E. coli assays, supporting its translational compatibility as a co-therapeutic agent. Combinations of 28510 with related analogs did not yield synergistic protection; 28510 alone remained the most effective compound. In silico absorption, distribution, metabolism, and excretion (ADME) predictions further confirmed its highly favorable drug-like properties, including excellent intestinal and oral absorption. Together, these findings establish 28510 as a first-in-class, non-MET-mediated otoprotective lead with broad efficacy and a favorable therapeutic profile, highlighting a new strategy for preventing AG-induced hearing loss.

External auditory canal cholesteatoma is a rare and potentially destructive otologic condition characterized by the accumulation of keratinizing squamous epithelium within the external auditory canal, leading to progressive bony erosion. Despite being described in the 19th century, EACC remains an uncommon and frequently underrecognized entity, often misdiagnosed as keratosis obturans or chronic otitis externa. Its pathogenesis is multifactorial and incompletely understood, involving impaired epithelial migration, chronic microtrauma, local inflammation, and ischemic changes of the canal skin. Clinical presentation is usually nonspecific and includes otalgia, otorrhea, aural fullness, and conductive hearing loss, contributing to diagnostic delay. Otoscopic examination typically reveals keratin debris associated with focal bone exposure. High-resolution computed tomography of the temporal bone plays a key role in evaluating bony erosion and disease extent; however, it lacks specificity for definitive tissue characterization, and magnetic resonance imaging may be useful in selected cases for differential diagnosis. We report the case of a 25-year-old patient with no relevant medical history who presented with persistent unilateral otorrhea of 3 months' duration, associated with severe otalgia and progressive hearing loss. A comprehensive clinical and radiological assessment suggested the diagnosis of primary external auditory canal cholesteatoma, which was subsequently confirmed by histopathological examination. The patient underwent surgical management with favorable clinical and functional outcomes. This case highlights the importance of a multidisciplinary diagnostic approach and early stage-adapted management to prevent complications and reduce the risk of recurrence.

Animal experiments have provided many insights on auditory function, notably in cases of sensorineural hearing loss (SNHL). However, it is not always clear how these findings translate to the human auditory system in clinically relevant contexts. Cross-species computational models of the auditory periphery can help bridge the gap between non-invasive human diagnostics and experimental evidence from animal studies. In this work we adapted a 1-D nonlinear cochlear transmission-line model designed for the human auditory periphery to mouse and gerbil, enabling a single computational framework for cross-species research on SNHL. Species-specific anatomical and physiological parameters - including basilar membrane (BM) length and width, stapes area, middle-ear transfer functions, and frequency range - were adjusted to match each species' auditory periphery and hearing range. Other cochlear parameters were calibrated to reproduce realistic cochlear tuning and compression. The adapted mouse and gerbil models were validated against experimental BM velocity level-growth characteristics, auditory-nerve (AN) tuning curves, and DPOAEs. Simulated AN outputs reasonably matched empirical measurements, including realistic AN thresholds and frequency selectivity. However, the discrepancy between simulations and measurements became larger for cochlear sections closer to the base or apex. Simulations of cochlear synaptopathy reproduced observed differences in recorded auditory brainstem and envelope following responses from mice and gerbils with SNHL. OHC individualization of the mouse model based on DPOAEs failed to faithfully reproduce individual measurements, although intergroup differences in OHC damage were captured. Our findings demonstrate that biophysically grounded auditory models can be translated across species while preserving realistic sound-coding properties and pathophysiological alterations.

The relationship between auditory input and cognitive development is fundamental, as early sensory deprivation can impair social communication and mimic neurodevelopmental disorders. Comprehensive audiological assessment is critical for children suspected of autism spectrum disorder to prevent "diagnostic overshadowing," where behavioral symptoms of hearing loss-such as social withdrawal and speech delay-are mislabeled as neurodevelopmental deficits. Although autism spectrum disorder involves social communication deficits under DSM-5 criteria, congenital progressive sensorineural hearing loss often presents with similar clinical features. Enlarged vestibular aqueduct syndrome is the most common congenital inner ear anomaly associated with progressive hearing loss and must be considered in differential diagnoses. This report describes a patient in his early teens, misdiagnosed with autism spectrum disorder for 8 years, whose diagnosis was corrected to enlarged vestibular aqueduct syndrome based on high-resolution imaging. Early identification is vital for timely interventions such as cochlear implantation.