Biochimica et biophysica acta. Molecular cell research最新文献

{"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}

{"title":"SYK overexpression enhances microtubule instability in an MDA-MB-231-derived paclitaxel-resistant cell line","authors":"Hsiao-Hui Kuo,&nbsp;Chien-Wei Huang,&nbsp;Wei-Rou Chiang,&nbsp;Chieh-Ting Fang,&nbsp;Shang-Yuan Liu,&nbsp;Ling-Huei Yih","doi":"10.1016/j.bbamcr.2025.120059","DOIUrl":"10.1016/j.bbamcr.2025.120059","url":null,"abstract":"<div><div>Paclitaxel resistance is a major obstacle to achieving long-term remission in patients with triple-negative breast cancer (TNBC), and effective strategies to overcome drug resistance would have significant clinical impact. In this study, we established a paclitaxel-resistant cell clone, T50R, from the human TNBC cell line MDA-MD-231. Intriguingly, these drug-resistant T50R cells required paclitaxel for proliferation. When cultured in the absence of drug, the cells exhibited high dynamic instability of microtubules (MTs) and spindle abnormalities, causing their accumulation in mitosis phase and cell death. Thus, the increased instability of MTs in T50R cells may contribute to the drug requirement for cell growth and drug-resistant phenotype, as paclitaxel counteracts the effect. Compared to the parental MDA-MD-231 cells, T50R cells had elevated expression of spleen tyrosine kinase (SYK), and inhibition or depletion of SYK in the T50R cells cultured without paclitaxel restored MT stability, reduced spindle defects and rescued cell death, suggesting that SYK overexpression contributes to the enhanced MT instability in T50R cells. Furthermore, T50R cells exhibited signs of ER stress and underwent ferroptotic cell death when cultured without paclitaxel, both of which could be ameliorated by inhibition of SYK. Finally, small molecules that target SYK or induce ferroptosis could significantly enhance T50R cell sensitivity to paclitaxel. Together, our results show that SYK-enhanced MT dynamic instability can play an important role in paclitaxel resistance and that targeting the SYK pathway may enhance paclitaxel response.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120059"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032429","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":"Intracellular calcium-induced ROS generation promotes squaraine phototoxicity","authors":"Giorgia Chinigò ,&nbsp;Carlotta Pontremoli ,&nbsp;Francesca Bianco ,&nbsp;Alessandra Gilardino ,&nbsp;Maria Jesus Moran Plata ,&nbsp;Alessia Brossa ,&nbsp;Benedetta Bussolati ,&nbsp;Sonja Visentin ,&nbsp;Nadia Barbero ,&nbsp;Alessandra Fiorio Pla","doi":"10.1016/j.bbamcr.2025.120055","DOIUrl":"10.1016/j.bbamcr.2025.120055","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved by the Food and Drug Administration (FDA) for the treatment of several pathological conditions, including cancer. Developing new photosensitizers (PSs) for PDT is of great interest to increase the treatment efficacy while minimizing side effects. In this regard, a better understanding of the signal transduction triggered by PS photo-activation may help to optimize PS efficacy.</div><div>In the present work, we synthesized a series of squaraines (SQs) featuring different indolenine ring modifications. Our results show that unsubstituted SQ has significant phototoxic activity, further increased by the introduction of a bromine in the indolenine ring (Br-SQ-C4) as well as the replacement of the squaryl oxygen atoms with sulfur atoms (SQ-S-C4). Phototoxicity positively correlates with higher photo-induced cytoplasmic Ca²⁺ signals as well as reactive oxygen species (ROS) generation. However, the different substituents strongly affect the signaling pathway triggered. The bromine substituent strengthens the localization of the dye in the endoplasmic reticulum (ER), while the sulfur substituent shifts its preferential localization to the mitochondria. Consistently, photo-activation of Br-SQ-C4 induces a larger ER Ca²⁺ release followed by SOCE, which fuels secondary ROS generation able to sustain a remarkable mitochondrial Ca²⁺ uptake and subsequent mitochondrial ROS generation. On the other hand, SQ-S-C4 can induce, already at the basal level, a greater perturbation of the Ca²⁺/ROS dynamics.</div><div>Overall, our results contribute to a deeper understanding of the intracellular signaling triggered by SQs, paving the way for the development of novel strategies aimed at increasing PDT efficacy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120055"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940718","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":"E3 ligase SMURF2 alleviated intrauterine adhesion by stabilizing SMAD6","authors":"Ke Zhou ,&nbsp;Yun Chen ,&nbsp;Lishi Chen ,&nbsp;Zhenfu Wu ,&nbsp;Lirong Zhang ,&nbsp;Jingjing Zheng ,&nbsp;Song Tian ,&nbsp;Mingzhu Wen ,&nbsp;Xin Li ,&nbsp;Huihua Cai","doi":"10.1016/j.bbamcr.2025.120045","DOIUrl":"10.1016/j.bbamcr.2025.120045","url":null,"abstract":"<div><div>Intrauterine adhesion (IUA) is a debilitating uterine disorder characterized by endometrial fibrosis and infertility, for which effective treatments remain limited. Here, we identify the E3 ubiquitin ligase SMURF2 as a critical protective factor against IUA progression. SMURF2 expression was significantly upregulated in endometrial tissues of IUA patients, a murine IUA model, and TGF-β1-treated human endometrial stromal cells (HESCs). Functional analyses revealed that SMURF2 overexpression mitigated fibrosis-associated phenotypes, including enhanced cell proliferation, migration, and extracellular matrix accumulation, both <em>in vitro</em> and <em>in vivo</em>, whereas SMURF2 knockdown had the opposite effect. Mechanistically, SMURF2 directly interacted with the inhibitory SMAD protein SMAD6 and promoted its stabilization via K63-linked polyubiquitination. Mutation analysis confirmed that disruption of the K63 linkage markedly reduced SMAD6 ubiquitination and destabilized the protein. As a result, SMAD6 accumulation suppressed TGF-β/Smad signaling and downstream fibrotic gene expression. These findings reveal a previously unrecognized SMURF2–SMAD6 axis that counteracts endometrial fibrosis, and suggest that enhancing SMURF2-mediated K63-linked ubiquitination may offer a novel therapeutic avenue for IUA treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120045"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871190","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":"Loss of Prominin 2 expression inhibits AKT/mTOR signaling to limit glycolysis and drive ferroptosis in breast cancer cells","authors":"Lei Yin ,&nbsp;Yanze Lin ,&nbsp;Zhongdian Yuan ,&nbsp;Rexiati Ruze ,&nbsp;Zhen Yang ,&nbsp;Yingmei Shao","doi":"10.1016/j.bbamcr.2025.120047","DOIUrl":"10.1016/j.bbamcr.2025.120047","url":null,"abstract":"<div><div>This study aimed to characterize the oncogenic functions of Prominin 2 (<em>PROM2</em>), the pro-cancer and ferroptosis resistance gene, in breast cancer (BC). <em>PROM2</em> expression was analyzed using single-cell RNA sequencing and the TCGA database. Its expression was confirmed in BC tissues and cell lines using qRT-PCR, immunohistochemistry, and western blot assays. The effects of <em>PROM2</em> were evaluated <em>in vivo</em> and <em>in vitro</em>. RNA sequencing and GSEA were used to investigate the potential underlying molecular mechanisms of <em>PROM2</em> in BC. Co-immunoprecipitation was used to determine the interaction between AKT and PROM2. <em>PROM2</em> expression was elevated in clinical samples and BC cells and positively correlated with a worse prognosis. Functional experiments demonstrated that <em>PROM2</em> silencing suppressed tumor growth and malignancy. Mechanistically, PROM2 interacts with AKT to activate mTOR signaling, thereby promoting glycolysis and inhibiting ferroptosis. Specifically, for glycolysis, <em>PROM2</em> silencing decreased glucose uptake, extracellular acidification rate, lactate production, and glycolysis-related enzyme expression, while increasing oxygen consumption. For ferroptosis, <em>PROM2</em> silencing upregulated reactive oxygen species, malondialdehyde, iron, Fe²⁺, and downregulated SLC7A11, GPX4, and glutathione levels. Overexpression of AKT or the AKT agonist (SC79) reversed the effects of <em>PROM2</em> silencing on BC cell glycolysis and ferroptosis. Our results suggest that <em>PROM2</em> is an oncogenic gene that supports BC progression by enhancing glycolysis and inhibiting ferroptosis <em>via</em> AKT/mTOR signaling. Therefore, <em>PROM2</em> may be a potential therapeutic target for BC treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120047"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862092","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":"Calcium-dependent regulation of physiological vs pathological cardiomyocyte hypertrophy","authors":"Joshua Chung ,&nbsp;Nathan Isles ,&nbsp;Stuart Johnston ,&nbsp;David J. Collins ,&nbsp;Julie R. McMullen ,&nbsp;H. Llewelyn Roderick ,&nbsp;Vijay Rajagopal","doi":"10.1016/j.bbamcr.2025.120046","DOIUrl":"10.1016/j.bbamcr.2025.120046","url":null,"abstract":"<div><div>Cardiomyocyte hypertrophic growth contributes to the adaptative response of the heart to meet sustained increases in hemodynamic demand. While hypertrophic responses to physiological cues maintains or enhances cardiac function, when triggered by pathological cues, this response is maladaptive, associated with compromised heart function, although initially, this response maybe adaptive with preserved function. Since cues and activated pathways associated with both forms of hypertrophy overlap, the question arises as to the mechanism that determines these different outcomes. Here we evaluate the hypothesis that cardiomyocyte Ca²⁺ signalling – a regulator of pathological hypertrophy – also signals physiological hypertrophy. We discuss how different Ca²⁺ profiles, in distinct subcellular organelles/microdomains, and interacting with other signalling pathways, provide a mechanism for Ca²⁺ to be decoded to induce distinct hypertrophic phenotypes. We discuss how integration of computational with rich structural and functional cellular measurements can be used to decipher the role of Ca²⁺ in hypertrophic gene programming.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120046"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871189","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":"SYT13: An underestimated synaptotagmin","authors":"Johannes Lehmann ,&nbsp;Alberto Catanese","doi":"10.1016/j.bbamcr.2025.120031","DOIUrl":"10.1016/j.bbamcr.2025.120031","url":null,"abstract":"<div><div>Synaptotagmin-13 (SYT13) is a non-canonical member of the of synaptotagmin family that, canonical synaptotagmins, doesn't contain Ca²⁺ binding sites, but still appears to play a key role in the control of different cellular processes such as vesicle transport, cell migration, signaling and cell development. The recent findings associate SYT13 with neuronal survival and development, metabolic homeostasis (especially insulin secretion) and both oncogenic and tumor suppressive function in multiple cancers. And yet all this data is scattered in fields, with no systematic review covering SYT13's detailed biology. A comprehensive literature review is therefore needed to explain SYT13's multifaceted roles, uncover informational gaps and direct future studies to exploit SYT13 as a target for neurodegeneration, metabolic disease and cancer therapy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120031"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749493","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":"Heat shock protein 70 regulates m6A modification in response to heat shock in esophageal squamous cell carcinoma.","authors":"Bin Du, Jia Wang, Jun Ma, Pu Wang","doi":"10.1016/j.bbamcr.2025.120027","DOIUrl":"10.1016/j.bbamcr.2025.120027","url":null,"abstract":"<p><p>Heat shock has been known to induce hyperplasia in esophageal epithelial cells. It is widely considered as a crucial risk factor in the initiation and development of esophageal squamous cell carcinoma (ESCC), yet our understanding of the underlying mechanisms remains limited. The m6A modification of mRNA plays a role in mediating several cellular processes and is critical during cell stress. Our study revealed that inhibiting of m6A 'writer' components of ESCC cells exhibit higher death rates and slower recovery after heat shock. After normalization using mRNA expression profiles, 91.08 % of significantly changed m6A modifications aligned with corresponding mRNA abundance changes, with no evidence of over-modification, while the increase in m6A modification of 8.92 % of heat-shock associated genes far exceeded the increase in mRNA (hyper - m6A modification), and A/U rich motifs were commonly observed in the 3'UTR of these gene. Inside the nucleus, the binding of HSP70s in m6A writer complex promote the hyper - m6A modification in specific mRNAs after heat shock. The stronger nuclear localization of HSP70 in ESCC tissues correlates with a poor prognosis for the patients. In conclusion, our research revealed that the nuclear HSP70 protein could bind to the METTL3/14 writer complex and regulate mRNA's m6A modification. Our results provide a new perspective for research into how HSP70 protein regulates mRNA stability and suggests a new direction for the comprehensive prevention and treatment of ESCC.</p>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":" ","pages":"120027"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717300","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}