ABSTRACT G protein–coupled receptors (GPCRs), the largest family of membrane proteins in mammals, are fundamental to olfactory signal transduction. By detecting odorant molecules and activating G protein–dependent and β‐arrestin–dependent signaling pathways, GPCRs regulate olfactory neuron depolarization, signal transmission, and adaptive modulation. This review comprehensively summarizes the molecular mechanisms of GPCRs in olfactory perception, signaling network regulation, and olfaction‐related disorders, including olfactory dysfunction, neurodegenerative diseases, and allergic inflammation. Furthermore, it highlights emerging therapeutic strategies such as biased ligands targeting GPCRs and stem cell–based interventions with clinical potential. Future investigations should prioritize elucidating the functions of orphan receptors and advancing precision therapeutic technologies to achieve breakthroughs in the diagnosis and treatment of olfaction‐related disorders.

Allergic rhinitis (AR) is a chronic airway inflammation driven by a type 2 immune response, yet the molecular mechanisms underlying its persistence and tissue remodelling remain incompletely understood. This study employed an integrated bioinformatics and experimental approach to systematically investigate the role of CLC (Charcot-Leyden crystal protein/Galectin-10) in AR pathogenesis. We identified CLC as a central hub gene through combined Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning (LASSO (Least Absolute Shrinkage and Selection Operator), SVM-RFE (Support Vector Machine-Recursive Feature Elimination)) of the GSE45323 dataset. Immune infiltration analysis revealed a strong positive correlation between CLC expression and M0 macrophage infiltration. Functional validation in IL-4-stimulated human nasal epithelial cells demonstrated that CLC knockdown significantly suppressed the expression of CCL26 (a potent eosinophil chemoattractant) and POSTN (a key mediator of tissue remodelling). This finding was corroborated in an OVA-induced murine AR model, where CLC was markedly upregulated in nasal mucosa. Our results reveal a novel CLC-CCL26/POSTN axis that concurrently orchestrates inflammatory cell recruitment and structural remodelling in AR, positioning CLC as a promising therapeutic target for intercepting disease progression.

Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway offers a promising immunotherapeutic approach to elicit potent antitumor immune responses. However, its therapeutic efficacy against head and neck squamous cell carcinoma (HNSCC) remains constrained by the paucity of endogenous dsDNA, antioxidant defenses, and inadequate tumor immunogenicity. To overcome these limitations, we developed calcium carbonate (CaCO3)-encapsulated copper/ manganese silicate nanospheres co-delivering the Toll-like receptor (TLR) agonist R848 as dual-amplified cGASSTING nanostimulators (CRC NPs) to potentiate antitumor immunotherapy. Tumor acidity triggers CaCO3 degradation, unleashing Ca2+ to overwhelm cellular calcium buffering and cripple tumor antioxidant systems. Simultaneously, mobilized cupric and manganese ions drive H2O2-to-ROS conversion via chemodynamic therapy, inflicting mitochondrial stress and liberating dsDNA. The release of R848 then activates TLR7/8-MyD88 signaling, promoting NF-kappa B nuclear translocation and IFN-I secretion, while synergizing with the NF-kappa B/ STING axis to enhance immune responses. In SCC-7 tumor-bearing mice, CRC NPs significantly potentiated antitumor immunity by activating the cGAS-STING pathway, thereby promoting dendritic cells maturation and T-cells infiltration to suppress tumor growth. This work establishes dual-amplified cGAS-STING nanostimulators as a promising therapeutic strategy for HNSCC.

Congenital middle ear malformations are a common hearing defect in newborns, primarily characterised by abnormal middle ear structures, particularly underdeveloped or malformed ossicular chains, resulting in conductive hearing loss. This article provides a comprehensive review of the embryonic development process of the middle ear and the genetic regulatory mechanisms, with a focus on the Tbx1 gene, which is closely related to middle ear development. Studies have shown that the Tbx1 gene plays a crucial role in the migration of neural crest cells and the formation of middle ear structures, and its mutation or abnormal expression can lead to developmental defects of the middle ear structure. These gene mutations affect downstream signalling pathways (such as FGF8 , FGF10 and BMP4 ), which are essential in the formation of the ossicles, ear canal and middle ear cavity. Additionally, this article discusses the aetiology of congenital middle ear malformations, associated syndromes, clinical manifestations, classification, diagnosis and treatment strategies. Diagnostic methods for middle ear malformations include audiological examinations, imaging studies and genetic testing. Early diagnosis and intervention, such as surgical correction and the use of hearing aids, can help improve the hearing and quality of life of patients. This article aims to provide a reference and basis for further etiological research and precise treatment by elucidating the mechanisms and clinical features of middle ear malformations.

In situ cancer vaccines have emerged as an attractive paradigm for cancer immunotherapy. Nevertheless, insufficient antigens production, weak antigen presentation and immunosuppressive tumor microenvironment impeded the effectiveness of tumor immunotherapy. Herein, we constructed the NLRP3 inflammasome mediated in situ cancer vaccine (FPLB), in which rod shaped α-Fe2O3@Pt schottky heterojunction loaded with lactate oxidase (LOx) and surface-modified with bovine serum albumin and folic acid conjugation (FA-BSA). On the one hand, FPLB NPs utilizes its physicochemical properties of high aspect ratio to induce the breakdown of dendritic cells (DCs) lysosomes and the release of cathepsin B, thereby activating the NLRP3 inflammasome. Besides, the formation of “circulating pump” by harnessing catalase (CAT) activity and LOx activity could continuously consume lactic acid to alleviate the inactivation of cytokines induced by lactic acid excess, thereby transforming inflammatory activators into controllable nanoadjuvants. On the other hand, the “circulating pump” not only catalyze continuous generation of pyruvic acid to block the cell cycle, but also boosts charge utilization efficiency for excellent sonodynamic therapy (SDT) effect under ultrasound irradiation, thereby inducing the apoptosis or necrosis of tumor cells and releasing tumor-associated antigens (TAAs). FPLB demonstrates a significant NLRP3-mediated anti-tumor immune response both in vitro and in vivo. This strategy provides a new paradigm for the construction of NLRP3 inflammasome-mediated in situ cancer vaccines, which will have profound implications for the application of immunotherapy.

Presbycusis, also known as age-related hearing loss (ARHL), is a progressive auditory impairment and ranks among the most prevalent sensory disorders in the elderly population. It is primarily caused by damage to hair cells, degeneration of spiral ganglion neurons, and atrophy of the stria vascularis, which are integral components of the cochlea. While extensive research has been devoted to hair cells and spiral ganglion neurons, this review focuses on the critical role of the stria vascularis in ARHL. The primary function of the stria vascularis is to maintain the endocochlear potential, which is essential for hearing. This review presents an overview of the research concerning the stria vascularis in ARHL, particularly focusing on the application of single-cell transcriptomics to elucidate its role. Furthermore, this review explores relevant signaling pathways and therapeutic strategies for ARHL. By enhancing the understanding of the stria vascularis in ARHL, this review aims to pave the way for personalized treatment and improved strategies for protection and prevention.

Background K-complexes, electroencephalographic markers of sleep protective mechanisms, may reflect cognitive impairment in obstructive sleep apnea (OSA). We investigated whether K-complex metrics (frequency, density, duration, amplitude) independently predict psychomotor vigilance in patients with OSA. Methods In 140 young and middle-aged adults, K-complexes were automatically detected via a U-Net neural network analyzing F3-M2 electroencephalogram recording. K-complex metrics, including frequency (Hz), density (events/min), duration (sec) and amplitude (μV), were measured. Psychomotor vigilance was assessed via standardized Psychomotor Vigilance Test (PVT). Hierarchical regression models evaluated associations between K-complex metrics and psychomotor vigilance, adjusted for age, education, and apnea-hypopnea index (AHI). Results K-complex metrics showed severity-dependent associations with psychomotor vigilance in young and middle-aged adults with OSA, meaning the nature of these associations predictably changed based on OSA severity. In patients with mild/moderate OSA, lower K-complex frequency (p = 0.011) was associated with better psychomotor vigilance. In patients with severe OSA, higher K-complex density (p = 0.019) and amplitude (p = 0.030) were independently associated with better psychomotor vigilance. K-complex metrics explained 15.2 % and 23.5 % additional variance in PVT Lapses in patients with mild/moderate and severe OSA, respectively. Age, education, and AHI further modulated psychomotor vigilance, particularly in patients with mild/moderate OSA. Conclusions K-complex density, frequency, and amplitude serve as severity-dependent neural biomarkers of psychomotor vigilance in young and middle-aged adults with OSA. These findings suggest the role of sleep metrics in psychomotor vigilance and highlight potential electrophysiological targets for intervention.

Age-related hearing loss (ARHL) is among the most prevalent and complex disorders in older adults. However, the pathogenesis of ARHL remains poorly understood. Using a single-cell transcriptomic landscape of mouse cochlea at five time points (1, 2, 5, 12 and 15 months), we found that the levels of human antigen R (HuR)—a classical RNA-binding protein—increase with age. Here we show that HuR is specifically transported from the nucleus to the cytoplasm in hair cells in both aging mice and nonhuman primates. HuR overexpression in cochlea could successfully alleviate ARHL in aged mice. Meanwhile, HuR deficiency led to premature hearing dysfunction characterized by degeneration of stereocilia and the subsequent loss of hair cells. RNA immunoprecipitation sequencing analysis revealed that HuR can bind to messenger RNAs that enable stereocilia maintenance, including Gnai3. Adeno-associated virus-mediated Gnai3 overexpression partially rescues the hearing defects in HuR-deficient mice. Taken together, these findings indicate that HuR is a potential therapeutic target for ARHL. Age-related hearing loss (ARHL) is a prevalent and complex disorder in older adults. Guo et al. identify human antigen R as a regulator of ARHL in aged mice and demonstrate that cochlear human antigen R overexpression alleviates ARHL, highlighting it as a therapeutic target for the condition.

Organoids, as a novel type of 3D spherical model, possess characteristics such as tissue heterogeneity, functional simulation capability, scalability, personalization, and strong compatibility. These features endow them with significant advantages in drug testing, including the ability to highly simulate human physiological and pathological characteristics, strong clinical relevance, high-throughput and rapid screening capabilities, avoidance of the limitations of animal models, and potential for personalized treatment. As a result, organoids have become an essential tool in drug development and precision medicine.In recent years, nasal organoids have been preliminarily established. These models have been utilized to elucidate the pathogenesis of chronic and acute sinusitis through nasal organoid inflammation models, as well as to screen allergens in allergic rhinitis. Additionally, olfactory epithelial organoid models have been employed to study the mechanisms of olfactory neuron damage and regeneration. This article reviews the recent advances in the fundamental research of nasal organoids and innovatively outlines a composite culture medium formulation developed by our laboratory, providing a new technical approach for cost-effective and efficient organoid research.

Atherosclerosis is a chronic inflammatory disease closely linked to immune dysregulation. The immune microenvironment within atherosclerotic lesions is highly complex, involving diverse innate and adaptive immune cells and their intricate crosstalk. These immune interactions collectively contribute to plaque formation, progression, and destabilization. This review comprehensively examines the roles of key immune cell populations—including macrophages, dendritic cells (DCs), neutrophils, mast cells, natural killer (NK) cells, T cells, and B cells—in regulating inflammation, foam cell formation, and lesion stability. Special attention is given to intercellular regulatory circuits such as the Th1–M1 feedback loop, the OX40L–Th17 axis, and DC–T–NK amplification loops. Furthermore, the review highlights the influence of immunometabolic reprogramming on immune cell function and plaque phenotype, illustrating how metabolic states shape inflammatory outcomes. It also discusses the contribution of key signaling pathways—including Toll-like receptors (TLRs), the NOD-like receptor protein 3 (NLRP3) inflammasome, and proprotein convertase subtilisin/kexin type 9 (PCSK9)—to atherosclerotic inflammation and plaque vulnerability. Advances in immunotherapy are also reviewed, including anti-inflammatory agents such as colchicine and canakinumab, as well as emerging vaccine strategies targeting lipid metabolism and vascular inflammation.A deeper understanding of immune cell interplay and signaling dynamics in atherosclerosis will provide a foundation for developing more effective, multi-targeted immunotherapeutic interventions. Future research should aim to refine these strategies to maximize efficacy and safety, with the goal of reducing the global burden of atherosclerotic cardiovascular disease.

Chondroid syringoma, a mixed tumor of the skin, is an acquired hamartoma that differentiates into hair follicles, sebaceous glands, and apocrine sweat glands. Chondroid syringoma in the ear region is exceptionally rare. However, we present 2 cases of ear chondroid syringoma: 1 involving multiple lesions in the external auditory canal and the other including a single lesion behind the auricle. We reviewed relevant literature to offer insights into the diagnosis and treatment of ear tumors in the future.

Cisplatin-induced peripheral vestibular toxicity can significantly affect the quality of life of cancer patients undergoing treatment. In this study, we established a model of cisplatin-induced vestibulotoxicity that demonstrated significant vestibular dysfunction, closely mirroring the condition of cancer patients receiving cisplatin treatment. Following cisplatin administration, type I and type II vestibular hair cells (vHCs) exhibited progressive loss, with type I vHCs showing greater susceptibility to the drug. In vestibular tissues treated with cisplatin, evidence was found for the induction of ferroptosis, as indicated by alterations in several key ferroptosis regulator genes and the activation of ferroptosis biomarkers. Furthermore, these phenotypes were ameliorated by the administration of Fer-1. In Atoh1-Gpx4-/- mice vHCs, increases in reactive oxygen species and Fe2+, along with reductions in mitochondrial cristae, cell membrane rupture, and cytoplasmic vacuolation, suggest the activation of ferroptosis. Notably, the phenotypes observed in Atoh1-Gpx4-/- mice closely resembled those induced by cisplatin in the utricle. Our findings also demonstrated that the FDA-approved madecassic acid effectively mitigates vHC loss resulting from Gpx4 ablation and cisplatin administration through the modulation of Acsl3 and Gpx4. In summary, inhibiting ferroptosis may represent a potential strategy to protect against vestibular dysfunction caused by cisplatin-induced vestibulotoxicity.

Inflammasome-mediated in situ cancer vaccines hold promise for cancer immunotherapy but are hampered by poor specificity to the tumor microenvironment (TME) and inadequate antigen-specific immune responses. Here, sequentially regulated transmutable nanoparticles (PEGCSMP NPs) are developed to enhance NLRP3 inflammasome activity and induce chemodynamic therapy (CDT) for robust adjuvant and antigens effects. Copper-manganese silicate nanoparticles (CSM NPs) are functionalized with molybdenum polyoxometalate (POM) clusters and ROS-cleavable poly(ethylene glycol) (mPEG) to form PEGCSMP NPs. Upon exposure to high ROS levels in the TME, PEGCSMP NPs shed their PEG layer, triggering aggregation and lysosomal rupture in dendritic cells (DCs) to activate the NLRP3 inflammasome. Meanwhile, high glutathione (GSH) levels in tumor cells degrade the aggregated particles, releasing metal ions that induce CDT to damage tumor cells and release tumor-associated antigens (TAAs). This dual mechanism of lysosomal assembly formation and degradation enhances antigen presentation and T cell activation for precise cancer immunotherapy.

Inflammation is among the known causes of cisplatin-induced hearing loss (CIHL), but its exact pathophysiological mechanisms remain unclear. Herein, we demonstrated that pyroptosis-a recently identified inflammatory type of regulated cell death dependent on gasdermin D (GSDMD)-was activated in the cochleae of cisplatin-treated mice, causing CIHL. Meanwhile, treatment with the GSDMD inhibitor necrosulfonamide alleviated CIHL in these mice. To further examine the role of GSDMD-mediated pyroptosis in CIHL, we conducted experiments in Gsdmd-deficient mice. Gsdmd-/- mice demonstrated significantly lower cisplatin-induced cochlear damage than control mice and appeared to be invulnerable to CIHL. Furthermore, GSDMD-mediated pyroptosis in the stria vascularis (SV), but not in the hair cells (HCs), played a dominant role in CIHL. In marginal cells (MCs) of SV, cisplatin induced caspase-dependent GSDMD cleavage, and the pore-forming N-terminal of GSDMD rapidly localized to the mitochondria, leading to abnormal mitochondrial aggregation and oxidative stress. The consequent mitochondrial dysfunction in MCs might result in the severe progression of inflammation, SV damage, and HC loss. Notably, the pharmacological inhibition of pyroptosis using the FDA-approved drug disulfiram effectively alleviated the symptoms of CIHL. Collectively, these findings offer a broad avenue for inhibiting pyroptosis-induced cisplatin ototoxicity and provide valuable theoretical insights for the clinical management of CIHL.

Objectives:We conducted this study to investigate the clinical outcomes of a new self-created technique for improving tympanoplasty. This technique, called the external auditory canal flap advancement method, aims to treat large tympanic membrane perforations, particularly those without residual edges at the anterior margin. Methods:We selected 30 patients (50 ears) with large tympanic membrane perforations located in the anterior part of the tympanic membrane without residual edges. We grouped these patients based on the surgical methods used. Twenty-six patients in the experimental group were treated with the new method of endoscopic transverse external auditory canal skin flap repair. The control group, consisting of 24 patients, received conventional endoscopic tympanoplasty. We assessed the patients for hearing, postoperative pain, and tympanic membrane healing both before and after the surgery. Results:Our new method significantly improves the success rate of tympanic membrane repair and hearing levels. The healing rate of tympanic membrane repair in the experimental group was 96.15% (25/26). Patient discharge time, postoperative pain, or recovery time was not affected. Conclusions:Endoscopic transverse external auditory canal flap nudge repair, as a complement to conventional otoscopic tympanoplasty, should be promoted in clinical practice.

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.

Proton sensing by G protein-coupled receptors (GPCRs) is crucial in many life activities. However, its underlying mechanism remains unclear. Here, we report 8 cryoelectron microscopy (cryo-EM) structures of human GPR4 and GPR68 at different pH values and in complex with Gs or Gq trimers or in apo state. Structural inspection, structure-based pKa calculations, and mutational and computational analyses revealed that protonation of two conserved extracellular histidines induced polar network formation and other conformational changes to tether 7-transmembrane (TM7) to second extracellular loop (ECL2), and these changes constitute the central mechanisms of proton-induced activation of GPR4 and GPR68. Unexpectedly, proton sensation by specific extracellular histidine determined biased G protein coupling of GPR4. Moreover, GPR68's additional pH-sensing H842.67 enhances its function in a more acidic optimal pH range. The propagation path connecting proton-sensing histidines to the toggle switch was characterized. Collectively, we provide structural insights into the proton sensing, activation, and downstream effector coupling mechanisms of proton-sensing GPCRs.

Age-related hearing loss (ARHL) is one of the most prevalent and complex disorders. Our previous study demonstrated that abnormal activation of mammalian target of rapamycin complex 1 (mTORC1) signaling in the cochlear neurosensory epithelium causes auditory hair cell (HC) damage and contributes to ARHL. However, the underlying mechanism of mTORC1 activation remains unclear. In this study, we identified tumor necrosis factor-alpha-induced protein 8-like 2 (TNFAIP8L2), an immune regulatory gene, as a potential candidate. To elucidate the effect of TNFAIP8L2 on mTORC1 signaling in the neurosensory epithelium and on hearing function, we generated a Tnfaip8l2-deficient (Tnfaip8l2-/-) mouse model. We discovered that Tnfaip8l2 deficiency led to features of oxidative stress in cochlear HCs and age-related hearing degeneration, exhibiting a similar phenotype to the mTORC1-over-activated Tsc1-cKO mice described previously. Furthermore, rapamycin, a well-known mTORC1 inhibitor, significantly mitigated the hearing dysfunction caused by Tnfaip8l2-deficiency. Mechanistically, we found that TNFAIP8L2 regulates mTORC1 signaling by simultaneously inhibiting the GTPase activity of Ras homolog enriched in brain (RHEB) and Ras-related C3 botulinum toxin substrate 1 (RAC1). Notably, both RHEB and RAC1 inhibitors alleviated the hearing phenotype observed in Tnfaip8l2-/- mice by inhibiting mTORC1 signaling. Collectively, our results provide insights into the activation of the mTORC1 pathway in aged mouse cochleae and positions TNFAIP8L2 as a valuable theoretical strategy.