ObjectiveMeniere’s disease is a disabling inner-ear disorder whose molecular basis remains poorly understood. Immune dysregulation and genetic susceptibility have been implicated in disease etiology, but the genes and immune-cell programs linking genetic susceptibility to disease-associated molecular alterations remain incompletely defined. Focusing on zinc transport and immune signaling, we aimed to prioritize genetically supported candidate genes and identify the immune-cell programs in which they are embedded.MethodsWe combined bulk peripheral blood transcriptomes, single-cell RNA sequencing of peripheral blood mononuclear cells, large-scale blood eQTL data, and genome-wide association summary statistics for Meniere’s disease. Differential expression analysis and WGCNA were used to define bulk transcriptional signatures, which were then integrated with scRNA-seq-derived cell-type marker genes to generate a candidate-gene set with complementary bulk disease-association and cell-type localization evidence. Two-sample Mendelian randomization and colocalization were applied to test whether genetically predicted expression of these candidate genes influences Meniere’s disease risk. Prioritized genes were then mapped to immune-cell subsets, ligand–receptor communication networks, and CD4+ T-cell differentiation trajectories at single-cell resolution, and their expression changes were validated at the mRNA and protein levels in an independent clinical cohort.ResultsBulk and single-cell analyses yielded 202 Meniere’s disease-associated candidate genes enriched in RNA processing, chromatin regulation, and immune-related pathways. Two-sample Mendelian randomization identified nominal associations between genetically predicted expression of SLC39A10, GAB1, and XCL2 and Meniere’s disease risk. Integration with bulk transcriptomic evidence prioritized increased SLC39A10 expression and reduced GAB1 and XCL2 expression for further analysis. Immune-signature enrichment and single-cell analyses localized their expression-related programs to CD4+ T cells, NK cells, monocytes, B cells, and other peripheral immune populations. CellChat and pseudotime analyses provided complementary descriptions of inferred intercellular communication and CD4+ T-cell state transitions. In an independent clinical cohort, SLC39A10, GAB1, and XCL2 showed concordant changes at the transcript and protein levels.ConclusionOur multi-layered genomic and single-cell analyses prioritize SLC39A10, GAB1, and XCL2 as candidate genes associated with Meniere’s disease and map their expression-related programs to CD4+ T-cell, NK-cell, and other peripheral immune compartments. Together, these findings support a putative zinc transport–immune framework that may contribute to systemic immune dysregulation in Meniere’s disease. This framework should be regarded as a hypothesis generated by integrative genomic and transcriptomic evidence and requires direct validation through measurements of zinc homeostasis, transporter activity, and downstream immune function.

Tinnitus is a prevalent and often persistent symptom that imposes a substantial psychological and functional burden. Beyond disease-related mechanisms, accumulating real-world observations suggest that tinnitus may also emerge as a manifestation of drug-related adverse events. However, systematic, cross-database evidence characterizing tinnitus-associated drug safety signals remains limited. This study identified 21 systemic medications previously reported in association with tinnitus and retrieved post-marketing reports from the FDA Adverse Event Reporting System (FAERS) (2004–2025) and the WHO VigiAccess database. After data cleaning and standardization, disproportionality analyses were performed using four complementary algorithms (reporting odds ratio, proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multi-item Gamma–Poisson Shrinker). Drug-event pairs meeting predefined thresholds were considered signals. We further conducted sex-stratified analyses, quantified the relative contribution of age, sex, and body weight to adverse events using an XGBoost model, and examined time-to-onset patterns with Weibull shape parameter modeling. Across databases, tinnitus-related adverse event signals were not randomly distributed but instead converged within specific system organ classes and formed recognizable clusters at the Preferred Term level, particularly within neuropsychiatric and musculoskeletal domains. Most reports originated from adult and older adult populations, with females being more frequently represented. Tinnitus appeared as a recurrent positive signal across multiple therapeutic categories, and a considerable proportion of signals overlapped between FAERS and VigiAccess, supporting robustness while revealing complementary differences between the databases. After stratification, several signals persisted across sexes, whereas age explained the greatest proportion of variability compared with sex and body weight. Moreover, time-to-onset analyses consistently suggested an early-failure risk pattern, in which adverse events occurred predominantly shortly after treatment initiation and then declined. Integrating two large pharmacovigilance databases, we mapped consistent risk signals for tinnitus across multiple medications. These findings support closer monitoring during early treatment and offer real-world evidence to guide safer prescribing and future mechanistic research.

With aging increases the possibility of body impairment, deafness prevention remains a major unmet clinical challenge, largely due to the lack of effective therapeutics capable of targeting cochlear hair cells (HCs) across the blood-labyrinth barrier (BLB). Here, we report a precisely structured palladium-polyoxometalate coordinated antioxidant nanoagent (Pd single-atom nanozyme, Pd SAN), which demonstrates superior antioxidative enzyme-like capacity and robust biosafety. With identical Pd1-O4 coordinating sites and controllable size, Pd SAN effectively penetrates the BLB, accumulates within the cochlea, and protects HCs from neomycin-induced damage. Mechanistically, Pd SAN inhibits ferroptosis by preserving glutathione redox balance, reducing lipid peroxidation, stabilizing lysosomal membranes, and maintaining Fe2+ homeostasis. Notably, dynamic simulation demonstrates that Pd SAN shows comparable binding affinity to critical HC proteins (Prestin, Myo7a) as superoxide dismutase (SOD), and functionally suppresses neomycin-induced ferroptosis with equal or greater efficacy. In vivo experiments confirm that Pd SAN prevents auditory threshold shifts and mitigates cochlear structural injury, underscoring its translational potential. This study not only reveals that lysosomal damage-iron metabolism dysregulation-oxidative stress is a key axis driving aminoglycoside ototoxicity, but also establishes Pd SAN whose structure can be accurately deciphered with mass spectroscopy as an innovatively designed cochlea-targeting antioxidant nanomaterial with strong potential for clinical translation in deafness prevention.

Rationale:Hearing loss is a common sensory disorder with few treatment options, mainly due to the blood-labyrinth barrier and lack of effective targeted delivery systems. Small molecules such as LLY283 and RG108 protect hair cells (HCs), but clinical use is limited by poor cellular uptake, off-target toxicity, and inefficient cochlear delivery. Methods:We developed a ferritin (Fn)-based nanocage (LR@Fn) to co-deliver RG108 and LLY283 via local injection through the round window membrane. Fn offers natural HC targeting, a hollow cavity, and good biocompatibility. Drugs were loaded using a pH-triggered strategy while maintaining structural and colloidal stability. Results:In neonatal cisplatin and adult noise-induced hearing loss models, LR@Fn reduced HCs loss, synaptic damage, and apoptosis more effectively than dexamethasone. LR@Fn treatment activated the Wnt/β-catenin pathway, which may contribute to the observed protective effect. Conclusions:LR@Fn is a biocompatible ferritin-based platform for targeted inner-ear therapy, showing potential for multiple forms of hearing loss.

Sensorineural hearing loss (SNHL) remains a major unmet clinical challenge due to the lack of effective strategies capable of protecting cochlear hair cells (HCs) from damage. Although aminoglycoside antibiotics are clinically indispensable, their ototoxicity can lead to irreversible HC loss. In this study, we established a mechanismoriented screening platform for natural compounds and identified Morroniside (Mor) from a library of 20 oxygen-containing small molecules as the most potent otoprotective candidate. Distinct from conventional antioxidants, Mor exhibited a strong predicted binding affinity toward cochlear target proteins based on molecular docking, and in vivo fluorescence tracing further demonstrated its preferential accumulation within the cochlea. Functionally, Mor markedly preserved auditory thresholds in vivo, as confirmed by auditory brainstem response (ABR) testing, and showed excellent biosafety in both histological and serum biochemical analyses. Mechanistically, Mor acted as a dual-pathway ferroptosis modulator, simultaneously: suppressing mitochondrial reactive oxygen species (mtROS) to maintain mitochondrial bioenergetic stability; stabilizing lysosomal membrane integrity to prevent lysosomal membrane permeability (LMP), thereby blocking iron-dependent lipid peroxidation. This dual-site regulation on mitochondria and lysosomes reveals an integrated ferroptosis-regulatory mechanism previously unrecognized in natural otoprotective agents. Altogether, our findings not only identify Mor as a promising and clinically approachable natural compound for preventing SNHL, but also provide a mechanistic framework for developing next-generation therapeutic interventions targeting organelle crosstalk-driven ferroptosis in the inner ear.

Nasopharyngeal carcinoma (NPC), a malignancy highly prevalent in East and Southeast Asia, is primarily treated with radiotherapy (RT). However, hypoxia-induced radioresistance presents a significant challenge. Nanozymes, nanomaterials with catalase-like activity, have emerged as a promising strategy for radiosensitization by converting elevated hydrogen peroxide in the tumor microenvironment into oxygen. Despite their potential, effectively targeting hypoxic lesions has been difficult. Here, we identify transferrin receptor 1 (TfR1) as an upregulated target in NPC, with its expression levels positively correlated with hypoxia. Human heavy-chain ferritin, a specific ligand of TfR1, selectively recognizes hypoxic NPC lesions in preclinical models. Based on these findings, we design a hypoxia-targeted nanozyme by loading platinum nanoparticles into ferritin. This nanozyme exhibits enhanced catalase-like activity and effectively alleviates tumor hypoxia in NPC xenografts. When combined with RT, a single injection of the nanozyme significantly inhibits tumor growth and prolongs mouse survival, outperforming sodium glycididazole, a clinically used radiosensitizer. In summary, our findings highlight TfR1 as an accessible cell surface target in hypoxic NPC lesions. The nanozyme targeting TfR1 holds promise for enhancing the therapeutic effectiveness of RT in NPC through an in situ oxygen-generation mechanism.

Nanodynamic therapy integrating the merits of different dynamic therapy for maximizing the reactive oxygen species (ROS) generation serves as a highly efficient anti-tumor strategy. Gaining dynamic insights into how nanomaterials modulate the anti-tumor performance guides the rational design of nano-drugs. Herein, over biocompatible CuSex nanoparticles which have been applied in photothermal therapy, Fe species are doped for modulating the absorption profiles for ROS and bandgap of CuSex, finally regulating the chemodynamic (CDT) and photodynamic (PDT) therapeutic performance. Experimental evidence demonstrates that Fe doped materials (FCS) endow the CuSex with enhanced photothermal efficiency, thus thermodynamically promotes the temperature-dependent peroxidase (POD)-like and oxidase (OXD)-like catalytic performance for transforming the abundant endogenous H2O2 into more highly toxic ROS. In addition, the dopant of Fe species decreases the bandgap of CuSex from 1.45 to 1.30 eV, suggesting that the PDT could be realized over FCS under the irradiation of redshifted NIR light, which is more clinically favorable. In vitro and in vivo experiments manifests that that FCS overtakes CuSex by effectively generating ROS storms under NIR light while depleting overexpressed GSH, inducing tumor cell death through dual pathways. This work offers a novel perspective for the design of smart-responsive nanomedicine.

Objective:To investigate the relationship between the Palatopharyngeal Arch Staging System（PASS） and the severity of Obstructive Sleep Apnea（OSA）, as well as the patterns of airway collapse, while further assessing its clinical applicability. Methods:A total of 98 patients diagnosed with OSA at the Department of Otorhinolaryngology Head and Neck Surgery, Shenzhen University Affiliated Shenzhen Hospital, were recruited for this study. Data collected included basic demographic information, oropharyngeal laryngoscopy videos, results from awake laryngoscopy Muller tests, and indicators from sleep respiratory monitoring. The distribution of each PASS stage among patients with varying severities of OSA was compared. Additionally, both objective and subjective sleep indicators along with occurrences of airway collapse in OSA patients across different PASS stages were analyzed. Results:In total, 98 patients participated in this study. Statistically significant differences were observed in neck circumference, weight, Body Mass Index（BMI）, tongue position, and PASS stage when comparing mild-to-moderate OSA patients to those with severe OSA（P<0.05）. Furthermore, there were statistically significant variations in Apnea-Hypopnea Index（AHI）, minimum blood oxygen saturation levels, average blood oxygen saturation levels, oxygen desaturation index values, and total oxygen desaturation indices among OSA patients categorized by different PASS stages. Multiple comparisons revealed statistically significant differences in AHI as well as minimum and average blood oxygen saturation levels between patients at PASS 1 versus those at PASS 3（P<0.05）. Additionally, notable differences regarding oropharyngeal collapse rates among OSA patients across various PASS stages were identified; specifically between those at PASS stage 1 and those at PASS stage 3. Conclusion:The proportion of PASS stages for OSA varies across different severity levels. The severity of OSA and the degree of airway collapse in patients with varying PASS stages also exhibit significant differences. Patients classified as PASS 3 demonstrate a more severe form of OSA compared to those at PASS 1, with stage 3 being more susceptible to oropharyngeal collapse than its stage 1 counterpart. This assessment system is anticipated to address the current limitations in evaluating the lateral pharyngeal wall within the oropharynx.

Platinum-based chemotherapy drugs, including cisplatin (CDDP), are known to cause irreversible hearing loss. We recently discovered that BRCA1 facilitates the repair of CDDP-induced DNA double-strand breaks (DSBs) in cochlear hair cells (HCs) and prevents hearing loss. However, the checkpoint pathways activated in response to DSBs in HCs, and the mechanisms by which Brca1 regulates these pathways, remain unclear. In this study, we demonstrate that CDDP induces significant DSBs in outer HCs (OHCs), accompanied by phosphorylation of ATM, CHK2, and p53 at serine‑15 (S15) and S20, leading to apoptosis. In contrast, CDDP induces fewer DSBs in inner HCs (IHCs), with phosphorylation of ATM and p53 at S20, but not CHK2, promoting cell survival. Brca1 deficiency further increases phosphorylation of ATM and p53 at S15 in CDDP-treated OHCs. In response to CDDP, phosphorylation of CHK2 is not detected, but phosphorylation of p53 at S20 is enhanced in Brca1-deficient OHCs, whereas, phosphorylation of p53 at S20 is significantly increased in both Brca1-deficient and proficient IHCs. The expression patterns of phosphorylated ATM, CHK2, and p53 in response to CDDP in cultured explants and cell lines differ markedly from those observed in Brca1-deficient and proficient mice in vivo. These findings suggest that CDDP induces extensive DSBs in OHCs, activating the ATM-CHK2-p53 pathway to promote cell death, while Brca1 deficiency exacerbates CDDP-induced DSBs and activates ATM-p53 signaling independent of CHK2, accelerating OHC loss. Additionally, these results demonstrate that CDDP induces modest DSBs in IHCs with activation of the ATM-p53 pathway, independent of CHK2 and BRCA1, leading to cell survival.

The competing endogenous RNA hypothesis offers new insights into tumour progression, yet its role in posttreatment nasopharyngeal carcinoma relapse remains unclear. This study constructed ceRNA networks to identify molecular markers associated with NPC relapse. Three pairs of primary and relapse NPC tissue samples, along with their matched adjacent tissues, were collected for the RNA and miRNA sequencing, screened and identified relapse-related specific differentially expressed genes. We identified relapse-specific differentially expressed genes and functional analyses revealed enrichment in translation, biosynthesis, metabolism, TCA cycle, cell cycle, p53 signalling and immune pathways. Then these relapse-associated differentially expressed mRNAs, lncRNAs, and miRNAs were utilised to construct regulatory networks, resulting in a ceRNA network comprising 813 mRNAs, 143 lncRNAs, and 24 miRNAs, along with a survival-associated subnetwork of 23 mRNAs. Key mRNAs, such as UBC, PLA2R1, PTPRO, SMC5, PFN2, TIMM17B, NT5E and PCSK5, were validated via qPCR in NPC cell lines and tissues. To our knowledge, this is the first study to construct a comprehensive ceRNA network specifically for posttreatment recurrent NPC. These findings highlight the ceRNA network as a valuable framework for elucidating the mechanisms of NPC relapse and for identifying potential biomarkers for prognosis and therapeutic targets in recurrent nasopharyngeal carcinoma.

Nanozyme-based catalytic therapy holds great promise for tumor treatment, but its clinical translation is often hampered by limited biocompatibility, poor targeting efficiency, and diminished catalytic performance under hypoxic conditions. In this study, we designed a multifunctional biomimetic nanozyme bioreactor (MEFR) by coassembling Fe3S4 nanozymes, M1-derived macrophage-derived exosomes (M1 Exos), and the hemoglobin allosteric effector RSR13. The MEFR exhibits strong peroxidase-like activity, efficiently catalyzing the conversion of endogenous H2O2 into cytotoxic hydroxyl radicals (·OH) for effective tumor cell elimination. The inclusion of RSR13 relieves tumor hypoxia, thereby enhancing the oxygen-dependent catalytic activity of the MEFR. Moreover, M1 Exos confer homotypic targeting and immunomodulatory effects by promoting the repolarization of tumor-associated macrophages from the M2 phenotype to the M1 phenotype. The MEFR exhibits efficient tumor accumulation, deep intratumoral penetration, and potent antitumor efficacy both in vitro and in vivo, with negligible systemic toxicity. This study presents a novel strategy for the construction of intelligent nanozyme platforms enabling precise and effective catalytic tumor therapy.

Nanozymes are nanomaterials with enzyme-like activities and have become a research hotspot in tumor therapy due to their exceptional properties. However, biological application of nanozymes remains a methodology and safety issue. More systematic and rational design of nanozymes is needed for better tumor treatment. In this Perspective, we focus on the key questions that need to be addressed in nanozyme research, including the catalytic mechanism elucidation and the construction of structure-activity relationship, and introduce several promising rational design methods as well as prospect the future development of nanozymes. This Perspective aims to help researchers clarify the rational design of nanozymes in tumor therapy, offering a comprehensive guide in this emerging field.

Cisplatin, a chemotherapeutic drug used to treat cancerous solid tumors, can result in ototoxicity due to serious toxic side effects resulting in irreversible hearing loss. Here, we investigated the effects of N6-methyladenosine (m6A) methylation on cisplatin-induced ototoxicity by using in vitro cochlear explants as a model system to explore the effect of the Methyltransferase-like 3 (METTL3) inhibitor STM2457 in ameliorating cisplatin-induced ototoxicity. STM2457 pretreatment was shown to significantly reduce reactive oxygen species (ROS) accumulation and the loss of hair cells (HCs) in different regions of the organ of Corti. STM2457 pretreatment led to significant reductions in TUNEL labeling, signifying a reduction in apoptosis. Additionally, expression of the apoptosis-related protein BAX was significantly decreased, while the ratio of BCL-XL was markedly increased. Transcriptomic measurements of the STM2457 + cisplatin group revealed significant enrichment of the Mitogen-Activated Protein Kinases (MAPK) signaling pathway, which when stimulated, could block the protective effect of STM2457 in cisplatin-treated HCs. Thus, we describe a mechanism by which STM2457 decreases cisplatin-related HC death in cochlear explants in vitro through activation of the MAPK pathway. This study reports for the first time that reducing RNA m6A methylation might protects against cisplatin-induced ototoxicity. Our data indicate that STM2457 can serve as an effect anti-apoptotic drug to decrease ototoxicity caused by cisplatin-induced ROS accumulation, effectively preventing cisplatin-induced hair cells loss.

Embedding hydrazine into graphenic networks, where two graphitic nitrogen atoms are directly linked by an N-N bond, endows unique redox activity and antiaromatic character, yet the construction of such fully fused architectures has remained a synthetic challenge. Here we report the first fully fused hydrazine-embedded nanographene (1) synthesized via a dehydrocyclization strategy. Single-crystal X-ray diffraction revealed a hydrazine moiety embedded within a fused polycyclic carbon framework measuring 1.4 nm diagonally with a helical saddle-shape. This π-extended architecture displays near-infrared (NIR) absorption (830 nm) and emission (879 nm, ΦF = 6.5%), as well as multistep redox processes accompanied by oxidation-induced planarization and an antiaromatic-to-aromatic transition. Chiral resolution further uncovered circularly polarized luminescence extending beyond 850 nm, which is observed for the first time from a helical nanographene. This study demonstrates that hydrazine embedment can be exploited to construct atomically precise nanocarbons with distinctive redox and NIR optical functions.

The clinical use of aminoglycosides often results in injury to vestibular hair cells and subsequent vestibular dysfunction. Thus, clarifying the targets and mechanisms underlying aminoglycoside-mediated damage is of urgent importance. Prostaglandin D2 synthase (Ptgds) is a glycoprotein that plays dual roles in lipid transport regulation and prostaglandin metabolism. However, the role of Ptgds in aminoglycoside-induced vestibular dysfunction remains unclear. This study aimed to explore the function of Ptgds in the utricle and HEI-OC1 cells. Neomycin injury induced high levels of Ptgds expression in utricle explants. Moreover, Ptgds knockdown protected against neomycin injury by enhancing cellular proliferation and viability while suppressing reactive oxygen species production, inflammation, and apoptosis. These findings suggest that Ptgds may serve as a novel therapeutic target for treating vestibular dysfunction caused by aminoglycoside-induced damage.

Cancer treatment faces challenges including drug resistance to intrinsic apoptosis pathways and the persistence of cancer stem cells (CSCs). The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces extrinsic apoptosis in tumor cells by binding to death receptors while sparing normal cells. TRAIL-based gene therapy has emerged as a promising solution to address the short half-life limitation of recombinant TRAIL proteins. To further enhance the therapeutic efficacy, combination strategies with TRAIL sensitizer salinomycin (Sali) appear to be particularly effective. Sali not only upregulates death receptor expression and reactive oxygen species (ROS) levels but also modulates CSC-related gene expression, contributing to its multifaceted antitumor activity. In this study, a micelle system was developed for co-delivery of TRAIL plasmids (pTRAIL) and Sali to tumor sites. γ-Polyglutamic acid (γ-PGA)-coating improved the in vivo stability profile of the co-delivery nanocomposites. The resulting co-delivery system (γ-PGA/Sali@P-S/pTRAIL) effectively induced apoptosis and suppressed CSC-associated gene expression in cervical cancer cells. Both in vitro and in vivo evaluations demonstrated the system's potent antitumor efficacy, highlighting its potential as a promising strategy for cervical cancer therapy.

Nanozyme-based immunogenic cell death (ICD) inducers that effectively induce a strong immune response via enzyme-like process have attracted great attention, but how to ensure controllable active sites and maximize site utilization remains a problem. Here, we report a structurally well-defined and highly functional single-site copper(I) nanomodulators termed CuNTD, constructed by precisely anchoring atomically dispersed self-assembly S-Cu(I)-S sites onto a two-dimensional Ti3C2 surface. Leveraging Cu+ with a higher catalytic efficiency than Cu2+, CuNTD generates reactive oxygen species (ROS) storms through photothermal-enhanced cascade catalysis, further inducing mitochondrial dysfunction, ferroptosis and cuproptosis. Multifunctional CuNTD triggers strong ICD through cascade-regulatory pathways of photothermal-amplified ROS storms, cuproptosis and ferroptosis, effectively promoting dendritic cell maturation while reducing monotherapies side effects and resistance. In vivo, CuNTD combined with FDA-approved immunoadjuvants significantly prolong the survival of mice. With its demonstrated biosafety and high efficiency as an ICD inducer, this study provides a promising framework for advancing augmented tumor immunotherapy with significant clinical potential.

Deafness and hearing loss are the most widely distributed sensory organ disabilities worldwide, and their negative impact places them at the top of the global burden of diseases list. Therefore, the need to develop new and efficient prevention and treatment strategies is urgent. Here, we successfully developed a noninvasive drug delivery system involving a ferritin (Fn)-based drug delivery platform. To further increase therapeutic efficacy, we loaded cimifugin (Ci), an active ingredient extracted from Cimicifuga racemosa, into Fn to form the complex Ci@Fn. Ci@Fn was injected through the retroauricular round window membrane and then transported to the basement membrane along with the flow of ectolymphatic and endolymphatic fluids. Further through the targeting function of Fn, Ci@Fn was able to precisely target hair cells (HCs). Subsequently, Ci@Fn is endocytosed by HCs and releases Ci in lysosomes, exerting its protective effect on HCs. Neonatal mouse model experiments revealed that Ci@Fn significantly reduced cisplatin (Cis)-induced cochlear hair cell damage and prevented hair cell loss and apoptosis. In addition, RNA sequencing analysis revealed that Ci@Fn attenuates Cis-induced ototoxicity mainly by modulating the PI3K-Akt signaling pathway. Finally, in validation experiments in an adult mouse model of noise-induced hearing damage, we found that Ci@Fn had a significant hearing-protective effect, superior to the current gold standard treatment (dexamethasone). These findings demonstrate that Ci@Fn is an innovative and efficient solution for hearing loss treatment and lays a solid foundation for future clinical applications.

Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive. In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA damage-inducing agent generates DNA damage in postmitotic HCs but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA damage-induced cell death and hearing loss.

Transmembrane protein 52B (TMEM52B), a newly identified tumor-related gene, has been reported to regulate various tumors, yet its role in nasopharyngeal carcinoma (NPC) remains unclear. Transcriptomic analysis of NPC cell lines reveals frequent overexpression of TMEM52B, and immunohistochemical results show that TMEM52B is associated with advanced tumor stage, recurrence, and decreased survival time. Depleting TMEM52B inhibits the proliferation, migration, invasion, and oncogenesis of NPC cells in vivo. TMEM52B encodes two isoforms, TMEM52B-P18 and TMEM52B-P20, differing in their N-terminals. While both isoforms exhibit similar pro-oncogenic roles and contribute to drug resistance in NPC, TMEM52B-P20 differentially promotes metastasis. This functional discrepancy may be attributed to their distinct subcellular localization; TMEM52B-P18 is confined to the cytoplasm, while TMEM52B-P20 is found both at the cell membrane and in the cytoplasm. Mechanistically, cytoplasmic TMEM52B enhances AKT phosphorylation by interacting with phosphoglycerate kinase 1 (PGK1), fostering NPC growth and metastasis. Meanwhile, membrane-localized TMEM52B-P20 promotes E-cadherin ubiquitination and degradation by facilitating its interaction with the E3 ubiquitin ligase NEDD4, further driving NPC metastasis. In conclusion, the TMEM52B-P18 and TMEM52B-P20 isoforms promote the metastasis of NPC cells through different mechanisms. Drugs targeting these TMEM52B isoforms may offer therapeutic benefits to cancer patients with varying degrees of metastasis.