BackgroundPerrault syndrome (PS) is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and primary ovarian insufficiency in females. LARS2, encoding mitochondrial leucyl-tRNA synthetase, is the most common causative gene for PS. However, the genetic spectrum and clinical variability of PS remain underexplored. Expanding the catalog of LARS2 variants and correlating them with phenotypic data are critical for delineating genotype-phenotype relationships.MethodsTwo unrelated Chinese probands with hearing loss were enrolled, and comprehensive clinical evaluations were performed. Whole-exome sequencing (WES) was used to identify genetic variants, followed by Sanger sequencing for family co-segregation verification. Minigene assays and RT-PCR were conducted to assess the splicing effect of the novel canonical splice-site variant LARS2 c.235-2A>G. For the novel missense variant LARS2 c.1661T>C, 3-D structural modeling and evolutionary conservation analysis were performed to evaluate its pathogenicity. Moreover, we comprehensively summarized all LARS2 variants associated with PS via an extensive literature review.ResultsProband 1 (12-year-old female) harbors compound heterozygous variants LARS2 c.235-2A>G (novel) and LARS2 c.880G>A, presenting with profound SNHL, primary ovarian insufficiency, and developmental delay. Proband 2 (7-year-old male) carries compound heterozygous variants LARS2 c.1661T>C (novel) and LARS2 c.1886C>T, manifesting severe SNHL with an unusual upsloping audiogram pattern and comprehension difficulties. Functional assays confirmed that LARS2 c.235-2A>G disrupts canonical splicing, leading to exon 4 skipping and in-frame deletions. 3-D structural modeling and conservation analysis revealed that LARS2 c.1661T>C likely impairs protein stability by altering residue interactions, with Val554 being highly conserved across species. According to the ACMG/AMP guideline, both novel LARS2 variants were classified as likely pathogenic.ConclusionWe identified two novel LARS2 variants associated with PS in Chinese patients, thereby expanding the LARS2 genetic spectrum and providing precise molecular evidence for clinical management and genetic counseling. This study enhances understanding of genotype-phenotype correlations in PS, thereby revealing the phenotypic heterogeneity of LARS2 variants.

Gap junction Beta 2 Protein (GJB2, Connexin26, Cx26), the primary genetic cause of hereditary hearing loss (25%-50% of cases), has been exclusively regarded as forming an intercellular channel that mediates rapid communication. Here, we redefine its biological role by discovering its nuclear localization and direct transcriptional regulatory function in cochlear structure development. We demonstrate that Cx26 could aggregate in the nucleus of cochlear support cell and cell lines. Cx26 can bind to the promoter transcription start point of genomic DNA and directly regulate gene transcription, thus controlling the structural development of the tunnel of Corti during cochlear development. Further, we provide strategies based on mechanisms to promote the TC development and hearing rescue in Cx26 deficient cochlea, which has important implications for the discovery and development of treatment strategies for hearing loss caused by Cx26 deficiency.

The ear, a highly sophisticated sensory organ responsible for detecting environmental sound waves, remains continuously at risk due to the high prevalence of otitis media (OM). This condition, primarily caused by pathogen invasion and the subsequent inflammatory cytokine storm, represents one of the most significant global health burdens, with estimated annual costs ranging from US $3 to $5 billion expenses. In response to this challenge, we have developed a sulfur-doped copper–zinc single-atom nanozyme (CuZn-NS SAzymes) that combines potent bactericidal capabilities with precise immunomodulatory functions. This nanozymes exhibit dual enzymatic activity: sulfur doping enhances peroxidase-like activity for enhanced bacterial killing, while subsequent catalase-like activity scavenges residual H₂O₂, establishing an “attack- and- self-protection” cycle. The nanozyme’s ultrasmall hydrodynamic diameter enhances cellular uptake, resulting in a marked reduction in pro-inflammatory cytokines and a simultaneous increase in anti-inflammatory mediators, effectively disrupting the oxidative-stress-inflammation axis. CuZn-NS SAzymes thus represent a promising therapeutic strategy for deep sensory organ infections. The ear is highly vulnerable to otitis media, a pathogen induced inflammatory disease that represents a major global health burden with substantial annual costs. Here, the authors develop a sulfur doped copper zinc single atom nanozyme with strong antibacterial activity and precise immunomodulatory functions.

BACKGROUND:Sleep apnea (SA), a widespread disorder linked to heart disease, affects > 1 billion people globally. Although fine particulate matter (PM2.5) is suspected to worsen this condition, the specific role of individual PM2.5 constituents-how genetics might amplify their harm-remains unclear. RESEARCH QUESTION:Are long-term exposures to PM2.5 constituents (elemental carbon [EC], organic matter [OM], sulfate, nitrate, and ammonium) associated with incident SA, and does genetic susceptibility modify these associations? STUDY DESIGN AND METHODS:In this prospective cohort study of 495,073 UK Biobank participants, PM2.5 constituents were modeled via the European Monitoring and Evaluation Programme model for the UK, driven by Weather and Research Forecast model meteorology. Time-dependent Cox regression and quantile-based g-computation (QGC) models were used for analysis. A genome-wide significant single nucleotide polymorphism (SNP), rs9937053, for SA identified in the UK Biobank database was selected to analyze its interaction with PM2.5 constituents. RESULTS:In the analysis of 495,073 participants with a median follow-up of 11.82 years, 7,086 incident cases of SA were identified. The adjusted hazard ratios (HRs) of SA for each increase in PM2.5, EC, OM, ammonium, nitrate, and sulfate were 1.16 (interquartile range [IQR], 1.15-1.18), 1.11 (IQR, 1.09-1.12), 1.08 (IQR, 1.07-1.09), 1.21 (IQR, 1.19-1.23), 1.18 (IQR, 1.17-1.19), and 1.11 (IQR, 1.09-1.12). QGC modeling identified sulfate as the predominant contributor to PM2.5-associated SA risk (58% proportion explained). Stratified analyses identified heightened susceptibility among urban residents (P < .05 for interaction for PM2.5 and nitrate) and individuals with obesity (BMI ≥ 30 kg/m2; P < .05 for interaction for PM2.5, EC, OM, ammonium, and sulfate). Moreover, the rs9937053 single nucleotide polymorphism significantly interacts with PM2.5 constituents on SA risk. INTERPRETATION:Our results show that PM2.5 constituents-particularly sulfate-elevate SA risk, with urban populations, individuals with obesity, and rs9937053 carriers at greatest vulnerability. These findings demonstrate SA risk resulting from PM2.5 exposure at concentrations exceeding the World Health Organization guidelines. They advocate for an urgent emission control of sulfate (gas and oil combustion) as a priority.

To establish consensus recommendations and standardized protocols for the clinical assessment and management of radiation-induced hearing loss (RIHL), a common yet potentially serious complication in nasopharyngeal carcinoma (NPC) patients receiving radiotherapy, for which effective treatments remain limited. A two-round Delphi survey was conducted with 19 Chinese experts from diverse specialties, including radiation oncology, medical oncology, radiology, and otorhinolaryngology. Utilizing a detailed items questionnaire that addressed diagnosis, prevention, and treatment aspects of RIHL, the panel formulated consensus recommendations. Additionally, the final recommendations were formulated based on the findings of the Delphi survey, in conjunction with evidence appraised using the GRADE system. During radiotherapy planning, the implementation of dose constraints for key auditory structures—namely the tympanic cavity, internal auditory canal and cochlea—was emphasized to preserve auditory function. Diagnostic evaluations were advised to comprise comprehensive assessments such as pure tone and speech audiometry, tympanometry, otoacoustic emissions, auditory evoked potentials, otoscopic examination, and CT/MRI imaging, with classification guided by the 2021 WHO grading criteria for type and severity. Therapeutic approaches should be customized based on disease stage and underlying etiology, incorporating strategies like Eustachian tube function restoration, management of otitis media with effusion, and tailored auditory rehabilitation. However, consensus on the applicability of most interventions was limited due to insufficient or conflicting evidence, underscoring the need for further research. This consensus provides a structured framework to standardize clinical assessment and management of RIHL, while laying a groundwork for future studies focused on optimizing patient outcomes.

Noise-induced hearing loss (NIHL) constitutes a growing global health burden, yet effective pharmacological interventions remain elusive. Current therapeutic development is severely constrained by two critical bottlenecks: the lack of rationally identified molecular targets and the absence of dosage forms tailored to the physiological barriers of the inner ear. Addressing these limitations, we propose an integrated precision therapy strategy. First, to overcome the unpredictability of drug selection, we employed a transcriptome-guided network pharmacology approach, which rationally identified GBR-12935 - a dopamine transporter (DAT) inhibitor - as a potent candidate capable of reversing the pathological gene signature of noise injury. However, as a central nervous system (CNS)-active agent, the clinical translation of GBR-12935 is hindered by its rapid clearance from the middle ear and the risk of off-target CNS effects due to the ear's anatomical proximity to the brain. To resolve this delivery dilemma, we engineered an injectable, in situ forming hydrogel specifically designed for sustained intratympanic administration. This biomaterial platform effectively prolongs drug residence time in the round window niche while minimizing systemic leakage, thereby maximizing local cochlear bioavailability and mitigating potential neurotoxicity. In a mouse model of severe acoustic trauma (110 dB SPL), the hydrogel-mediated delivery significantly outperformed free drug administration. Quantitative immunofluorescence revealed that this localized intervention not only prevented the loss of cochlear ribbon synapses but, crucially, inhibited the pathological enlargement and aggregation of surviving ribbons, maintaining their morphological stability against excitotoxic edema. This structural preservation translated into robust functional recovery, evidenced by attenuated Auditory Brainstem Response (ABR) threshold shifts (15 dB rescue at 24 kHz, P < 0.01 vs. noise). Collectively, our study establishes a closed-loop paradigm combining computational prediction with rational biomaterial design, providing a potent and safe non-steroidal auditory protection strategy for addressing cochlear synaptopathy.

Background/Objectives: Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder caused by recurrent upper-airway collapse during sleep, leading to intermittent hypoxia, sleep fragmentation, and excessive daytime sleepiness. Although continuous positive airway pressure (CPAP) remains the first-line therapy, long-term adherence is often suboptimal, underscoring the need for more tolerable and flexible treatment options. This review aims to summarize the pathophysiological rationale for pharmacotherapy in OSA and to discuss recent developments in drug-based interventions. Methods: We conducted a narrative review of the literature on pharmacological interventions for OSA, with a systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov up to 4 August 2026. We included randomised controlled trials, observational studies, meta-analyses, and mechanistic human or animal studies that reported relevant sleep and respiratory outcomes, and graded evidence according to the principles of GRADE framework. Results: Several drug classes have shown promise: agents that increase upper-airway dilator muscle activity, respiratory stabilizers that reduce loop gain, medications that raise the arousal threshold, topical anti-inflammatory drugs for mucosal edema, and systemic metabolic modulators such as glucagon-like peptide-1 receptor agonists and dual incretin receptor agonists. Emerging strategies, including gene therapy directed at the hypoglossal motor system, are also under investigation at the preclinical stage. Moreover, combining pharmacotherapy with CPAP or other devices can produce synergistic benefits, enabling lower device pressures and enhanced patient comfort. Conclusions: Pharmacotherapy for OSA is progressively moving from exploratory research towards targeted, phenotype-driven personalized treatment. Future studies should focus on robust patient phenotyping, multi-mechanistic combination regimens, and long-term clinical outcome evaluations to facilitate the integration of drug-based therapies into routine OSA management, particularly in specific subgroups such as those with COMISA.

To quantify the impact of the implementation of the "Healthy China 2030" Planning Outline on the scale expansion of medical and health resources in China, and to assess the dynamic changes of such resources before and after the policy intervention. Data for this study were obtained from the China Health Statistics Yearbook covering the period from 1990 to 2023. In October 2016, the Chinese government officially issued the Healthy China 2030 Planning Outline. A total of 13 indicators across 3 dimensions (human resources, physical resources, and financial resources) were selected for this study, specifically: number of hospitals, number of hospital beds, number of health personnel, number of health technicians, number of licensed (assistant) physicians, number of registered nurses, as well as the per 1,000 population counterparts of the above human resource indicators; additional financial indicators included total health expenditure, per capita health expenditure, and government health expenditure. Segmented regression analysis under the interrupted time series (ITS) analysis framework was applied to evaluate the changing trends of medical and health resources in China from 1990 to 2023, with a focus on the characteristics of scale changes in such resources before and after the implementation of the Outline. Autocorrelation of the outcome indicators was first assessed via residual plots, the reliability of the results was further verified using the Durbin-Watson test, and the Newey-West method was subsequently applied to correct the standard errors. To ensure the robustness of the study findings, sensitivity analyses were performed respectively by setting 2017 as the alternative intervention start point and excluding data from the COVID-19 pandemic period (2020-2023). Interrupted time series analysis showed that after the implementation of the "Healthy China 2030" Planning Outline, the scale of China's medical and health resources continued to expand and showed a significant growth trend (all P < 0.05): the number of hospitals increased steadily from 1990 to 2023, with a growth coefficient of 0.082 (95% CI: 0.060-0.103) after the policy implementation; the number of hospital beds showed a significant upward trend (coefficient = 20.687, 95% CI: 16.001-25.373); the growth coefficients of human resource indicators all increased significantly, among which the growth coefficient of health personnel was 0.429 (95% CI: 0.363-0.495), health technical personnel was 0.429 (95% CI: 0.375-0.484), licensed (assistant) physicians was 0.181 (95% CI: 0.164-0.198), and registered nurses was 0.223 (95% CI: 0.195-0.251), while the growth coefficients of indicators related to per 1,000 population ranged from 0.133 to 0.309; When the financial resource indicators were analyzed in absolute terms, all indicators of financial resources showed a rapid increasing trend: total health expenditure increased by an average of 495.552 (95% CI: 450.222-540.882) billion yuan annually, per capita health expenditure increased by an average of 342.651 (95% CI: 310.002-375.301) yuan annually, and government health expenditure increased by an average of 116.142 (95% CI: 95.688-136.596) billion yuan annually. After log-transformation of the financial resource indicators, the results showed that the annual relative growth rate of total health expenditure decreased by 0.060 (95% CI: -0.072 to -0.047), the annual relative growth rate of per capita health expenditure decreased by 0.054 (95% CI: -0.065 to -0. 043), and the annual relative growth rate of government health expenditure decreased by 0.090 (95% CI: -0.104 to -0.076) after the intervention. These findings indicate that although the absolute scale of health investment continued to expand, its relative growth rate slowed down, reflecting that China's health investment has become more rational, efficient and sustainable, which is consistent with the policy goal of pursuing high-quality development and curbing unreasonable growth. Sensitivity analyses further verified the robustness of the main findings. The implementation of the Healthy China 2030 Planning Outline is positively associated with the significant growth in the total scale of medical and health resources and the level of per capita accessibility in China, with multiple indicators having reached the 2030 targets set out in the Outline ahead of schedule. This study, based on a quasi-experimental analysis of long-term national-level data, provides robust empirical evidence for the evaluation of the policy effects of national health strategies. Looking ahead, it is necessary to dynamically adjust the policy focus, maintain sustained attention to the fiscal sustainability of health investment and the long-term mechanism for health workforce training, so as to promote the high-quality development of medical and health resources.

With further research on the relationship between gut microbiota and human health, discussions on various gut-X axis have been increasingly prevalent. Evidence indicates that microbiota dysbiosis is closely linked to the onset and progression of audiovestibular disorders and the gut-ear axis has gradually been recognized as a vital systemic regulatory pathway. This article systematically reviewed the interaction mechanisms between microbiota dysbiosis and audiovestibular diseases, intervention strategies, research limitations and future perspectives. This axis functions mainly through immune-mediated barrier damage, metabolic disorder and neurotransmitter crosstalk. Modulation of the gut microbiota can alleviate symptoms of certain audiovestibular disorders. This review aims to provide novel insights for the pathogenesis, intervention and clinical management of audiovestibular disorders.

Epidemiological studies have revealed a correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and auditory dysfunction. Here, we demonstrate that intranasal infection of K18-ACE2 mice with four SARS-CoV-2 strains (original, Delta, BA.1, and BA.2) enables the virus to directly invade the inner ear, specifically targeting spiral ganglion neurons (SGNs), leading to increased phase separation and apoptosis in SGNs. Direct infection with different SARS-CoV-2 strains can cause intracellular phase separation and increased neuronal cell apoptosis. Overexpression of the spike protein, mediating viral entry into host cells by binding to cell surface receptors, induces the aberrant aggregation of GTPase-activating protein-binding protein 1 (G3BP1)-positive stress granules by inhibiting the mTOR signaling pathway. This mechanism drives phase separation in neuronal cells and ultimately results in increased apoptosis. Our study unveils an inflammation-independent pathway for SARS-CoV-2-induced hearing loss, centered on direct SGN infection and spike-protein-driven dysregulation of stress granules, thereby providing a critical theoretical foundation for developing targeted therapeutic strategies.

Abstract Background Hereditary deafness is a common sensory disorder in infants and children. Gene therapy has achieved major clinical breakthroughs in OTOF ‐related deafness, establishing proof of concept for treating monogenic hearing loss. In contrast, GJB2 ‐related hearing loss remains more challenging because of its broad cochlear expression, complex supporting‐cell targets, developmental involvement, and narrow therapeutic window. Methods We reviewed recent advances in hereditary deafness gene therapy, focusing on the translational progression from OTOF to GJB2 . We summarize early inner‐ear gene‐therapy efforts, clinical and preclinical developments in OTOF ‐targeted therapy, and current GJB2 ‐directed strategies, including gene replacement, cell‐specific delivery, base editing, pharmacological rescue, and potential in utero intervention. Results OTOF gene therapy has progressed to clinical trials, with dual‐adeno‐associated‐virus strategies producing substantial and durable hearing restoration in patients with DFNB9. Its success is supported by preserved cochlear architecture and efficient inner‐hair‐cell targeting. GJB2 therapy remains at the preclinical or early‐clinical stage. Major barriers include the broad distribution of connexin 26‐expressing cells, the need for precise supporting‐cell targeting, limitations of current disease models, developmental differences between mice and humans, and irreversible cochlear abnormalities before postnatal treatment. Conclusion OTOF provides an important translational framework, but GJB2 requires distinct strategies involving precise cochlear delivery, controlled transgene expression, improved models, large‐animal validation, and potentially earlier intervention.

BACKGROUND:Hereditary hearing loss is one of the most common disabling disorders in children and lacks effective pharmacological treatments. Recent breakthroughs in OTOF gene therapy clinical trials necessitate standardized frameworks to guide emerging therapies. This study aims to establish the first international consensus on the clinical application of gene therapy for hereditary hearing loss. METHODS:A modified Delphi process was conducted from March 2024 to March 2025, involving 46 multidisciplinary experts from several countries across otology, genetics, audiology, gene therapy, and hearing rehabilitation. After a systematic literature review, as well as integration of research and clinical expertise and experience, three iterative voting rounds (two anonymous surveys and one online consensus meeting) were performed. Statements required ≥75% agreement for inclusion. FINDINGS:From 9,093 publications, 69 were used to draft and support the consensus statements. A total of 30 statements relevant to six domains achieved consensus on gene therapy for hereditary hearing loss, including ethical review (1 statement), patient selection criteria (12 statements), diagnosis and preoperative evaluation (9 statements), gene therapy drug delivery (4 statements), follow-up (3 statements), and post-treatment auditory and speech rehabilitation (1 statement). CONCLUSIONS:This consensus provides the first globally endorsed framework for gene therapy in hereditary hearing loss. It standardizes clinical trial design and patient management, accelerating translation from research to practice while ensuring safety. The guidelines are immediately applicable to OTOF-related hearing loss and adaptable to other genetic forms. FUNDING:This work was supported by the National Natural Science Foundation of China, the German Research Foundation (DFG) via the Cluster of Excellence, and others.

王秋菊: 随着人口老龄化进程的加快,老年性听力损失与认知障碍的共病现象逐渐引起临床与科研领域的高度重视.大量研究提示,听力下降不仅影响老年人沟通能力与生活质量,还可能与认知功能减退呈显著相关,甚至在一定程度上加速痴呆的发生与发展.

Hearing and vision are the most important sensory functions. Genetic studies have revealed that specific genetic mutations can concurrently induce auditory and visual dysfunction. The comorbid deafness-blindness prevent mutual sensory compensation, thereby severely delaying speech, cognitive, and intellectual development in affected pediatric patients and imposing a profound burden on their families. In this review, we summarize the currently identified genes that cause hearing and vision impairments and classify them based on their pathological mechanisms. Furthermore, recent advances in gene therapy have brought new hope for the definitive treatment of genetic hearing loss and visual impairment, and relevant clinical trials have demonstrated promising therapeutic efficacy. Therefore, we also summarize the latest progress of gene therapy and ongoing clinical trial programs targeting these otooculopathies, aiming to provide references and basis for the subsequent treatment of comorbid auditory and visual dysfunctions.

GJB2-associated hearing loss is the most common form of non-syndromic hereditary deafness worldwide. However, it exhibits significant heterogeneity in terms of both clinical presentation and biological basis. This review focuses on mechanism-oriented therapeutic strategies for GJB2-associated hearing loss, investigating how different types of GJB2 variants correspond to distinct clinical phenotypes and underlying pathogenic mechanisms, and aims to determine appropriate treatments. Current evidence suggests that GJB2-associated hearing loss is not solely caused by channel dysfunction resulting from gap junction defects, but rather the result of multiple pathological processes, including impaired GJB2 transcriptional regulation, cochlear developmental abnormalities, sensory epithelial degeneration and secondary damage pathways such as inflammation. Consequently, emerging therapeutic approaches can be viewed as interventions targeting specific mechanisms, including gene therapy, restoration of protein transport and pharmacological modulation of damage to the cochlear microenvironment. Overall, this review highlights the importance of aligning therapeutic strategies with specific GJB2 variants, underlying pathogenic mechanisms, and the developmental window during which cochlear injury remains biologically reversible.

Connexins are essential for cellular communication and play a critical role in various physiological processes, including hearing. Connexin26 (Cx26), encoded by the GJB2 gene, is a key component of cochlear gap junctions and is vital for potassium recycling and ATP release-both of which are vital for auditory function. Mutations in GJB2 are the primary cause of sensorineural hearing loss. However, the phenotypic variability observed in individuals with the same mutation suggests the involvement of other complex regulatory factors. While the regulatory mechanisms of Connexin43 have been extensively studied, research on the mechanisms of Cx26 remains limited. This review summarizes the reported regulatory mechanisms of GJB2 from multiple perspectives, both pre- and post-transcription, in an effort to explore ways to regulate connexin expression and provide new insights into gene therapy for diseases caused by alterations in connexin levels.

For patients with severe and profound hearing loss, cochlear implant (CI), a common and effective modality for restoring hearing, directly stimulates spiral ganglion neurons (SGNs) to generate electrical activity and form auditory perception. However, the postoperative outcome of CI is significantly influenced by the number of surviving SGNs, ​​which is a key focus of preoperative evaluation​​. Existing audiologic function and radiographic tests cannot directly demonstrate the integrity of inner ear primary neurons. In this study, ​​we developed and validated​​ a radionuclide-labeled anti-vesicular glutamate transporter 1 (anti-VGLUT1) antibody-drug and achieved animal-level in vivo imaging of cochlear SGNs using nuclear imaging. By screening the public single-cell sequencing database, it is found that VGLUT1 can serve as a representative cell membrane marker for SGN in the cochlea. The potential of anti-VGLUT1 conjugated to the long half-life 177Lu as a molecular probe to detect the relative number of SGNs in SGN-injured mouse and pig models is explored. The study provides a novel method for assessing cochlear nerve integrity in vivo by visualizing target antigen expression levels through nuclear imaging. This approach is promising to help CI candidates with preoperative inner ear SGN integrity assessment, contributing to clinical decision-making.

Intracellular calcium increase and neurotransmitter release in vestibular hair cells (VHCs) play central roles in equilibrioception, which is one of the basic senses essential for daily life activities and movement in mammals. Independent of mechano-electrical transduction (MET), whether Gq protein-coupled receptor (GqPCR) signaling participate in the regulation of intracellular calcium dynamics and induce neuronal transmitter release in hair cells remains unknown. We screened mechanosensitive GqPCRs in VHCs and found that a Class C GPCR, metabotropic glutamate receptor 2 (mGlu2), is expressed in kinocilia and is essential for normal balance. Notably, the dispensable role of mGlu2 in normal hearing is consistent with absent of mature kinocilia in cochlea hair cells. Different from the conventional mGlu2-Gi signaling, the sensing of mechanical signals by mGlu2 activates the Gq‒PLCD4 pathway, increases intracellular calcium concentration and promotes neurotransmitter release in VHCs. Hair cell-specific deficiency of either Grm2 or Gnaq , or knockdown of Plcd4 expression, but not deficiency of another GqPCR Gpr68 , causes significant balance deficits. Reintroduction of mGlu2 into the VHCs of Pou4f3-CreER +/− Grm2 fl/fl mice restore vestibular functions. Our study reveals a previously uncharacterized role of GPCR signaling in equilibrioception and provides important insight into kinocilia signaling in VHCs, which are absent in mature cochlear hair cells.

Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system. Liquid–liquid phase separation (LLPS) is a physiological process that facilitates the reversible and dynamic assembly of biomolecular condensates. Increasing evidence suggests that LLPS plays a significant role in the pathogenesis of hereditary hearing loss. Nevertheless, there is a conspicuous lack of systematic investigations exploring the impact of LLPS abnormalities on the etiology of hereditary hearing loss. In this review, we examine the mechanisms by which dysfunctions in LLPS contribute to hereditary hearing loss, specifically focusing on its effects on mechanoelectrical transduction in hair bundles, transcriptional regulation, post-transcriptional modifications, the actin cytoskeleton, ion homeostasis within the inner ear, and energy and redox homeostasis. Furthermore, we evaluate the considerable potential of targeting LLPS as a therapeutic approach for hearing loss and propose innovative perspectives on LLPS that may guide future research initiatives in the field of auditory disorders.

The calcium- and integrin-binding protein (CIB) family, comprising four evolutionarily conserved members (CIB1, CIB2, CIB3, and CIB4), is characterized by canonical EF-hand motifs. The functions of CIBs in the inner ear have been investigated, although further research is still necessary to gain a comprehensive understanding of them. Among the CIB family members, CIB2 is essential for auditory function. CIB3 and CIB2 jointly participate in the regulation of balance. Beyond their sensory roles, CIBs exhibit multifunctionality through calcium-dependent interactions with diverse molecular partners, contributing to the pathogenesis of various conditions, including neurological disorders, cardiovascular diseases, cancer, and male infertility. In this review, we discuss the conserved structure of the CIB family, highlighting its contributions to various biological functions. We also summarize the distribution and function of the CIB family, emphasizing the pivotal roles of CIB2 and CIB3 in hearing and balance.