Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"O-GlcNAcylation of DDX46 promotes hepatocellular carcinoma progression by activating the PI3K/Akt signaling pathway","authors":"Qiujie Wang,&nbsp;Yuanyuan Liu,&nbsp;Kai Wang,&nbsp;Ailong Huang,&nbsp;Ni Tang,&nbsp;Pai Peng","doi":"10.1016/j.bbamcr.2025.120080","DOIUrl":"10.1016/j.bbamcr.2025.120080","url":null,"abstract":"<div><div>O-linked-β-<em>N</em>-acetylglucosamine (O-GlcNAc) modification, also known as O-GlcNAcylation, is a dynamic and reversible protein modification. Aberrant O-GlcNAcylation are associated with the pathogenesis of cancers. DEAD-box helicase 46 (DDX46) is an ATP-dependent RNA helicase associated with cancer development; however, its role and regulation in hepatocellular carcinoma (HCC) remain unclear. In this study, we observed that the level of O-GlcNAcylation of DDX46 was significantly elevated in HCC mouse models and patients. In addition, direct OGT-DDX46 interaction facilitates O-GlcNAcylation at the Ser257 site. Mechanically, we discovered that O-GlcNAcylation enhances the stability of DDX46 by impeding ubiquitin-mediated degradation. Increased expression of DDX46 activates the PI3K/Akt signaling pathway, promoting the proliferation and invasion of HCC. Taken together, our study highlights the critical role of DDX46 O-GlcNAcylation in HCC progression, thus proposing targeted disruption of this cascade as a novel therapeutic strategy for HCC treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 1","pages":"Article 120080"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH2-mediated hypermethylation of H3K27me3 downregulates claudin-4 and upregulates the Wnt/β-catenin signaling pathway in hepatocellular carcinoma metastasis","authors":"Smriti Verma ,&nbsp;Manisha Yadav ,&nbsp;Shobhit Verma ,&nbsp;Anurag Kumar Srivastava ,&nbsp;Madhav Nilakanth Mugale","doi":"10.1016/j.bbamcr.2025.120076","DOIUrl":"10.1016/j.bbamcr.2025.120076","url":null,"abstract":"<div><div>Enhancer of zeste homolog 2 (EZH2) is often overexpressed in malignant tumors and plays a key role in metastasis by trimethylating lysine 27 on histone H3 (H3K27me3). However, the exact mechanism by which EZH2 facilitates metastasis in the diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR)-induced hepatocellular carcinoma (HCC) model remains unexplored. In this study, we demonstrated that EZH2 expression is elevated in HCC and is associated with metastasis to lung tissue, with poor overall survival outcomes. EZH2 overexpression in HCC liver tissues inhibited claudin-4 gene expression and promoted the activation of the Wnt/β-catenin signaling pathway. β-catenin signaling activates Lymphoid Enhancer-Binding Factor 1(LEF-1) transcription factors that regulate the expression of genes involved in epithelia-to-mesenchymal transition (EMT) and metastasis. EZH2 overexpression significantly elevates H3K27me3 at the promoter, suppressing claudin-4 expression. This leads to increased levels of Matrix metalloproteinase-9 (MMP-9) and vimentin, enhancing the invasion, migration, and metastasis of hepatocellular carcinoma (HCC) cells. However, inhibiting EZH2 with tazemetostat subsequently enhanced claudin-4 expression by reducing Wnt/β-catenin signaling activity and inhibiting EMT-inducing factors.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 1","pages":"Article 120076"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequent EPHA2 receptor mutations in cholangiocarcinoma disrupt receptor forward signaling supporting a tumor suppressor role","authors":"Evodie Koutouan ,&nbsp;Alejandro Lillo ,&nbsp;Ayano Kabashima ,&nbsp;Jack W. Sample ,&nbsp;Danielle Carlson ,&nbsp;Rondell Graham ,&nbsp;Rory L. Smoot ,&nbsp;Elena B. Pasquale","doi":"10.1016/j.bbamcr.2025.120081","DOIUrl":"10.1016/j.bbamcr.2025.120081","url":null,"abstract":"<div><div>Although EPHA2 is a receptor tyrosine kinase widely expressed in many cancers, it exhibits a uniquely high frequency of coding sequence mutations in cholangiocarcinoma, a cancer of the biliary tract with dismal prognosis. EPHA2 is extensively studied, but very little is known about the role of EPHA2 cancer mutations. To define the functional significance of EPHA2 mutations in biliary tract cancers, we generated representative EPHA2 mutants and monitored major receptor autophosphorylation sites as indicators of kinase activity-dependent signal transduction (known as forward signaling). We found that missense mutations in the ligand-binding domain abrogate ephrinA ligand binding, while missense mutations in the kinase domain abrogate kinase activity. The effects of missense mutations in other domains were less pronounced and varied depending on the phosphosite. The majority of the EPHA2 mutations are nonsense or frame-shift mutations that introduce early stop codons. They generate EPHA2 truncated forms that lack an intact kinase domain or, in some cases, most of the coding sequence. Several EPHA2 mutants tested inhibited tyrosine phosphorylation of co-expressed EPHA2 wild-type, indicating the ability to exert dominant negative effects. We show that EPHA2 forward signaling in cholangiocytes inhibits the ERK oncogenic pathway and cell proliferation, suggesting that loss-of-function mutations facilitate tumor development in the biliary tract. Indeed, an EPHA2 kinase-inactive mutant, but not EPHA2 wild-type, induced proliferative masses consistent with well differentiated cholangiocarcinoma in a validated mouse model of cholangiocarcinogenesis. Thus, EPHA2 has the attributes of a driver gene with tumor suppressor activity in biliary tract cancers.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 1","pages":"Article 120081"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Importin α/β1 dependent nuclear import of black sea bass polyomavirus large tumor antigen is mediated by a classical NLS located downstream of the SF3 helicase domain","authors":"Mikayla Hoad ,&nbsp;Silvia Pavan ,&nbsp;Sepehr Nematollahzadeh ,&nbsp;Ole Tietz ,&nbsp;Jospeh Reeman ,&nbsp;Jade K. Forwood ,&nbsp;Gualtiero Alvisi","doi":"10.1016/j.bbamcr.2025.120074","DOIUrl":"10.1016/j.bbamcr.2025.120074","url":null,"abstract":"<div><div>Polyomaviruses (PyVs) are small dsDNA viruses replicating in the host cell nucleus, thanks to the viral encoded large tumor antigen (LTA). Aided by recent advances in molecular biology techniques, the list of known PyVs is rapidly growing, revealing unexpected broad sequence, and host heterogenicity. Given their dependence on nuclear localization, LTAs represent an attractive model for studying the nuclear transport process. A comprehensive analysis of the evolution of classical nuclear localization signals (cNLSs) within LTAs encoded by PyVs infecting mammals highlighted strong positional conservation of cNLSs between the LXCXE motif and the origin-binding domain (OBD). Here we extend such analysis to PyVs infecting non-mammalian hosts. We combined biochemical, structural and functional assays to demonstrate that black sea bass (BSB) PyV-LTA is transported into the nucleus by the Importin (IMP)α/β1 heterodimer thanks to the recognition of a bipartite cNLS located downstream of the SF3 helicase domain, rather than between the LXCXE motif and the OBD. Such cNLS binds with high affinity to several IMPα paralogs by simultaneously interacting with the minor and major binding sites. Substitution of NLS key basic residues abrogating binding to IMPα, or co-expression with the well characterized IMPα/β1 inhibitor Bimax2 suppressed nuclear localization. Intriguingly a cNLS could be identified in a similar position in LTAs from other PyVs infecting ray-finned fishes, but not cartilaginous fishes, birds or scorpions, where cNLSs were predicted elsewhere. Our study suggests that LTAs from PyVs infecting different non-mammalian hosts might bear cNLS in distinctive positions, possibly reflecting processes of virus-host adaptation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 1","pages":"Article 120074"},"PeriodicalIF":3.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-22-3p suppresses hair regrowth in androgenetic alopecia by targeting chloride intracellular channel 4","authors":"Haijing Fu ,&nbsp;Chenxi Wu ,&nbsp;Tianyi Xu ,&nbsp;Wumei Zhao ,&nbsp;Leiwei Jiang ,&nbsp;Shijun Shan","doi":"10.1016/j.bbamcr.2025.120033","DOIUrl":"10.1016/j.bbamcr.2025.120033","url":null,"abstract":"<div><div>Androgenetic alopecia (AGA), the most prevalent form of patterned hair loss, manifests through androgen sensitivity, age-dependent progression, and genetic predisposition. Emerging evidence highlights microRNAs as critical post-transcriptional regulators in hair follicle pathophysiology. This study used human hair follicle stem cells (HFSCs), hair follicle samples of AGA patients and AGA mouse model to explore the role of miR-22-3p/CLIC4 signaling in AGA. A significant rise in miR-22-3p expression was observed in balding hair follicles of grade 5 AGA patients. Then we identify chloride intracellular channel 4 (CLIC4) as a novel target of miR-22-3p and CLIC4 is markedly low expressed in balding hair follicle of AGA patients. Functional studies demonstrated that knockdown CLIC4 (shCLIC4) impaired HFSCs proliferative capacity and disrupted sonic hedgehog (SHH) pathway activation, evidenced by decreased Gli1 and Gli2 transcriptional activity. These findings establish the miR-22-3p/CLIC4 axis as a novel regulator of hair follicular miniaturization, proposing CLIC4-mediated SHH modulation as a potential therapeutic target for AGA intervention.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120033"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The late stages of yeast mitoribosome large subunit biogenesis","authors":"Sorbhi Rathore ,&nbsp;Julian Conrad ,&nbsp;Dasmanthie De Silva ,&nbsp;Alberto Ferrari ,&nbsp;Danielle Bouquio ,&nbsp;Hyung-Jun Kim ,&nbsp;Roger Salvatori ,&nbsp;Andreas Linden ,&nbsp;Olexandr Dybkov ,&nbsp;Henning Urlaub ,&nbsp;Martin Ott ,&nbsp;Antoni Barrientos","doi":"10.1016/j.bbamcr.2025.120051","DOIUrl":"10.1016/j.bbamcr.2025.120051","url":null,"abstract":"<div><div>The <em>Saccharomyces cerevisiae</em> mitoribosome synthesizes eight mitochondrial DNA-encoded proteins essential for oxidative phosphorylation. Mitoribosome large subunit (mtLSU) biogenesis involves the conserved DEAD-box helicase Mrh4 and the GTPases Mtg1/GTPBP7 and Mtg2/GTPBP5. Here, we have employed genetic, biochemical, in vitro reconstitution, and cryo-EM approaches to elucidate their hierarchical action during the late stages of mtLSU assembly. We show that Mrh4-mediated bL33m incorporation precedes Mtg1 recruitment to the 21S rRNA. Cryo-EM structures of mitoribosome assembly intermediates accumulating in the absence of Mtg1 or uL16m reveal that Mtg1 restructures the 21S rRNA H73-75 and H93 domains to their mature fold. This subsequently allows the structuring of neighboring peptidyl transfer center region helices and the incorporation of uL6m, uL16m, bL35m, and bL36m during late mtLSU maturation. Unexpectedly, monosomes containing immature mtLSU assemble in Mrh4-, bL33m-, uL16m-, Mtg1-, and Mtg2-depleted mitochondria, at levels that increase with the maturation state of the mtLSU particle. Our data have shed light on the rRNA folding events and the structuring of the MRPs that occur during the late stages of assembly. They have provided insight into the roles of assembly factors Mrh4, Mtg1, and Mtg2 during the process and revealed evolutionarily conserved mechanisms underlying mitochondrial ribosome assembly.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120051"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GJB2 promotes ovarian cancer progression and cisplatin resistance by upregulating TNC expression","authors":"Jiaxuan Zhao ,&nbsp;Yunfei Lu ,&nbsp;Kun Yang ,&nbsp;Linfeng Zhou ,&nbsp;Haoran Fu ,&nbsp;Yingying Sai ,&nbsp;Jinghua Wu","doi":"10.1016/j.bbamcr.2025.120058","DOIUrl":"10.1016/j.bbamcr.2025.120058","url":null,"abstract":"<div><div>Cisplatin resistance continues to be a major obstacle in the treatment of ovarian cancer (OC). Gap junction protein β-2 (GJB2), a key member of the connexin family, is well-known for its association with hereditary deafness. However, its role in ovarian cancer chemotherapy resistance remains unexplored. In this study, we found that increased expression of GJB2 was observed in OC patients with poor prognosis and in cisplatin-resistant OC cells. GJB2 knockdown in OVCAR-3 cells inhibited cancer progression and enhanced cisplatin sensitivity via increased drug uptake, while GJB2 overexpression promoted tumor progression and cisplatin resistance. Furthermore, a positive correlation between GJB2 and TNC expression was identified in clinical tissue samples. TNC knockdown in GJB2-overexpressing cells eliminated GJB2-driven OC progression and cisplatin resistance. Finally, epicatechin enhanced drug uptake mediated cisplatin sensitivity by inhibiting the GJB2 expression. This study demonstrates that GJB2 is a potential therapeutic target for overcoming cisplatin resistance in OC by upregulating TNC expression. Epicatechin may enhance cisplatin efficacy by targeting GJB2.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120058"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer","authors":"Sweta H. Makwana ,&nbsp;Jyoti Poswal ,&nbsp;Pooja Yadav ,&nbsp;Shailendra P. Singh ,&nbsp;Chandi C. Mandal","doi":"10.1016/j.bbamcr.2025.120052","DOIUrl":"10.1016/j.bbamcr.2025.120052","url":null,"abstract":"<div><div>Cancer cells often undergo metabolic reprogramming, typically increasing their uptake and utilization of energy sources like glucose, fatty acids, lactate, glutamine, and pyruvate, while maintaining redox balance. Rather than relying on oxidative phosphorylation, cancer cells preferentially engage glycolysis to convert pyruvate into lactate. This metabolic reprogramming correlates with altered glucose metabolism and dysregulated insulin signalling. Diabetes is associated with increased risk of certain cancer types. Cancer database analysis of genes involved in glucose metabolism, insulin signalling and diabetes, identified an unexplored differentially expressed <em>PHKA1</em> gene associated with poor patient survivability in breast cancer. Expression of the <em>PHKA1</em> gene was found to be upregulated under an environment of high glucose and insulin in cancer cells. Silencing <em>PHKA1</em> via siRNA led to marked decrease in proliferative, invasion, migratory, and stem-like properties of MDA-MB-231 and MCF-7 breast cancer cells. Experimental findings demonstrated reduced expression of mesenchymal markers (e.g., Vimentin, Zeb-1/2), cell cycle markers (e.g., CDK-2/4), and proliferative markers (e.g., Bcl-2 and Bcl-xl), while expression of epithelial markers (e.g., E-cadherin and Keratin-19) were enhanced in <em>PHKA1</em> knockdown cells when compared to control. Performance of glycolysis stress and mito stress assay further demonstrated that siPHKA1 cells had diminished glycolytic activity alongside suppressed mitochondrial function. These findings highlight intricate relationship between metabolic dysregulation observed in diabetes, contributing to the progression of cancer. Collectively, these observations highlight <em>PHKA1</em> as an oncogenic candidate with potential role in breast cancer. Comprehensive understanding of such metabolic alterations is critical to designing targeted therapeutic strategies aimed at mitigating breast cancer progression.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120052"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of translocon-associated protein subunit beta (TRAPβ) stimulates cell cycle arrest and apoptosis in human colorectal cancer cells","authors":"Darshika Amarakoon,&nbsp;Jing Peng,&nbsp;Cheng-I Wei,&nbsp;Seong-Ho Lee","doi":"10.1016/j.bbamcr.2025.120057","DOIUrl":"10.1016/j.bbamcr.2025.120057","url":null,"abstract":"<div><div>Translocon-associated protein subunit beta (TRAPβ), also known as signal sequence receptor 2 (SSR2) serves as an auxiliary protein facilitating co-translational translocation in the endoplasmic reticulum (ER); however, its role in colorectal cancer is unknown to date. The objectives of the current study are to examine if <em>TRAPβ/SSR2</em> knockdown affects the cell proliferation and to elucidate mechanisms by which TRAPβ/SSR2 regulates proliferation of human colorectal cancer. We silenced <em>TRAPβ/SSR2</em> transiently and stably in human colorectal cancer cell lines and analyzed cell proliferative properties. Transient transfection of <em>TRAPβ/SSR2</em> siRNA significantly repressed the viability of five different types of human colorectal cancer cells. Flow cytometry and western blot showed that <em>TRAPβ/SSR2</em> knockdown led to significant increase of G2/M-phase arrest in SW480 cells and S-phase arrest in HCT116 and DLD-1 cells. Annexin V-fluorescein isothiocyanate and propidium iodide staining showed that <em>TRAPβ/SSR2</em> knockdown significantly induced apoptosis in SW480, HCT116, and DLD-1 cells. Similarly, SW480 stable cells with <em>TRAPβ/SSR2</em> knockdown showed a significant inhibition of anchorage-independent cell growth, an increase of G2/M-phase arrest with downregulation of cyclin B1, and increase of apoptosis. Regarding mechanisms, <em>TRAPβ/SSR2</em> knockdown mitigated epidermal growth factor-stimulated activation of mitogen-activated protein kinase (MAPK) pathways and showed significantly decreased expression of inositol-requiring enzyme 1 alpha (IRE1α), while <em>IRE1α</em> reintroduction in <em>TRAPβ/SSR2</em> knockdown cells reversed G2/M-phase arrest and promoted cell cycle progression. All taken together, our data demonstrate that TRAPβ/SSR2 in the ER could be a molecular target to control cell cycle progression and apoptosis through MAPK-mediated and IRE1α-mediated pathways in human colorectal cancer cells.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120057"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into early cochlear damage induced by potassium channel deficiency","authors":"Ezequiel Rías ,&nbsp;Camila Carignano ,&nbsp;Valeria C. Castagna ,&nbsp;Leonardo Dionisio ,&nbsp;Jimena A. Ballestero ,&nbsp;Giuliana Paolillo ,&nbsp;Ingrid Ouwerkerk ,&nbsp;María Eugenia Gomez-Casati ,&nbsp;Guillermo Spitzmaul","doi":"10.1016/j.bbamcr.2025.120030","DOIUrl":"10.1016/j.bbamcr.2025.120030","url":null,"abstract":"<div><div>Hearing loss (HL) is the most common sensory disorder, caused by genetic mutations and acquired factors like presbycusis and noise exposure. A critical factor in HL development is the dysfunction of potassium (K⁺) channels, essential for sensory cell function in the organ of Corti (OC). Inner and outer hair cells (IHCs and OHCs) convert sound into electrical signals, while supporting cells (SCs) maintain ionic and structural balance. KCNQ4 channels, located in the basal membrane of OHCs, regulate K⁺ efflux. Mutations in KCNQ4 are linked to progressive HL (DFNA2), noise-induced hearing loss, and presbycusis, leading to K⁺ accumulation, cellular stress, and OHC death. Gene editing or pharmacological activation of KCNQ4 has shown potential in partially preventing HL in mouse models. In this study, we demonstrate KCNQ4 deletion disrupts the localization of key proteins like prestin and BK channels, alters OHC organization, and induces apoptosis in sensory and SC. Spiral ganglion neurons (SGNs) also degenerate over time. Despite these structural changes, noise exposure does not exacerbate OHC damage in our KCNQ4-deficient model. This highlights KCNQ4's role in maintaining ion homeostasis and cochlear function, as its absence triggers widespread dysfunction in the OC. The present study demonstrates that disruptions in a single cell type can have a cascade effect on overall cochlear health. Understanding the molecular and cellular consequences of KCNQ4 mutations is crucial for developing targeted therapies to mitigate progressive HL caused by genetic and environmental factors.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120030"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}