Cellular signalling最新文献

{"title":"MicroRNA-93-5p alleviates uric acid-induced fibrosis in renal tubular epithelial cells by regulating the SMAD5/Id2 signaling pathway","authors":"Xun Lu ,&nbsp;Chengxin Ma ,&nbsp;Dongxiao Li ,&nbsp;Jianan Yang ,&nbsp;Yuheng Sun ,&nbsp;Bowen Liu ,&nbsp;Binghai Zhao ,&nbsp;Hongzhi Li","doi":"10.1016/j.cellsig.2025.112081","DOIUrl":"10.1016/j.cellsig.2025.112081","url":null,"abstract":"<div><div>Hyperuricemia (HUA) is a prevalent metabolic disorder that contributes significantly to renal injury and may lead to the development of chronic kidney disease. Although previous studies have explored this condition, the molecular mechanisms underlying HUA-induced renal damage, particularly the role of small RNAs, remain inadequately understood. This study aimed to investigate the potential role of microRNA-93-5p (miR-93-5p) in HUA-associated renal injury. A comprehensive analysis was conducted to examine changes in miR-93-5p expression and its target gene, SMAD5, using knockout mouse models, cell cultures, transgenic techniques, and molecular biology methods. The findings demonstrated a significant upregulation of miR-93-5p in both HUA models and clinical serum samples, with a strong correlation to renal injury. Deletion of miR-93-5p resulted in increased SMAD5 expression and improved renal function, indicating that miR-93-5p contributed to renal injury by suppressing SMAD5 and promoting partial epithelial-mesenchymal transition in renal tubular epithelial cells. Transcriptomic analysis further revealed that miR-93-5p regulated numerous genes associated with inflammation, fibrosis, and apoptosis. Overall, these results underscore the pivotal role of miR-93-5p in HUA-induced renal damage through modulation of the SMAD5/Id2 signaling pathway, offering valuable insights into kidney disease pathophysiology and identifying potential therapeutic targets for clinical intervention.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112081"},"PeriodicalIF":3.7,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893286","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":"In vitro and in ovo characterization of Ewing sarcoma cell lines: Comparison with neuroblastoma cell lines and lymphatic endothelial cells","authors":"Jürgen Becker,&nbsp;Cherim Jeon,&nbsp;Jörg Wilting","doi":"10.1016/j.cellsig.2025.112072","DOIUrl":"10.1016/j.cellsig.2025.112072","url":null,"abstract":"<div><div>Ewing sarcoma (EwS) is characterized by a balanced chromosomal translocation in which a member of the FET gene family is fused with an E26 transformation specific (ETS) transcription factor: the most common fusion being EWSR1–FLI1. Traditionally, EwS includes Ewing-like tumors, Askin tumors, and peripheral primitive neuroectodermal tumors (PNET), indicative of a neuroectodermal relationship. Previously, in the absence of genetic diagnostics, extraosseous EwS could be mistaken for neuroblastoma (NB), which has become particularly clear in the history of the CHP100 cell line. In previous studies we characterized the behavior of NB cell lines in the chick chorioallantoic membrane (CAM) assay. Here we focused on four EWSR1-FLI1 gene-fusion-transcript-containing EwS cell lines (CHP100, TC71, RH1, SK-N-MC) and compared them to NB cell lines. We show that EwS cells form highly aggressive CD99- and vimentin-positive tumors in CAM, with blood-filled cysts, very similar to NB tumors in CAM. We observed newly formed blood vessels in the tumors, but not lymphangiogenesis. However, the main characteristics were arrosion of blood vessels and hemorrhage. At RNA and protein level we found important differences between EwS and NB cell lines (23 NB cell lines were used for qPCR studies): Adrenergic receptor ß1 (a potential therapeutic target) was exclusively found in EwS. In contrast, VANGL2, LRP5, PROX1, HAND2, PHOX2A and PHOX2B were found in NB cells, with few exceptions only. EWSR1, FLI1, ERG, CD99 and vimentin are characteristically expressed in lymphatic endothelial cells (LECs). Previously, EWSR1-FLI1-silencing studies revealed critically regulated genes in a mixture of cells containing mesenchymal stem cells. By whole genome RNASeq, we found 32 of 38 of these genes in LECs. With gene set enrichment analysis of publicly available data sets, we found increased similarity of EWS-FLI/ERG-silenced EwS cell lines with LECs and blood vascular ECs. In sum, EwS tumors in CAM recapitulate the high aggressiveness of the malignancy. EwS and NB cell lines show characteristic molecular differences despite similar behavior in CAM. EwS and ECs show a certain degree of molecular similarity, and the original description of EwS as an endothelioma of bone should still be considered as a possibility. We discuss our data in the light of the little work that exists on the innervation and lymphatic supply of bone.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112072"},"PeriodicalIF":3.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902329","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":"LOH12CR2 activated by sodium butyrate suppresses tumorigenesis in colorectal cancer via METTL14-mediated N6-methyladenosine modification of SPC24 mRNA","authors":"Yanbing Lin ,&nbsp;Qianwen Zhou ,&nbsp;Mengqi Li ,&nbsp;Sucheng Hou ,&nbsp;Jia Xu ,&nbsp;Dongfang Dai ,&nbsp;Xiaoqin Yuan","doi":"10.1016/j.cellsig.2025.112079","DOIUrl":"10.1016/j.cellsig.2025.112079","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Epidemiological studies suggest that dietary fiber intake reduces CRC risk, with butyrate, a fermentation product of dietary fiber, showing promising anti-cancer properties. However, the underlying molecular mechanisms remain poorly understood. In this study, we reveal that sodium butyrate (NaB) upregulates the long non-coding RNA LOH12CR2 in CRC cells, which is crucial for NaB's anti-tumor effects both in vitro and in vivo. Our transcriptome sequencing and subsequent functional analyses demonstrate that LOH12CR2 mediates NaB’s impact by inhibiting the mitotic regulator SPC24, which is overexpressed in CRC. Mechanistically, LOH12CR2 interacts with and stabilizes the m6A methyltransferase METTL14, enhancing m6A modification and subsequent degradation of SPC24 mRNA. We identify a novel LOH12CR2-METTL14-m6A regulatory axis in CRC, through which NaB exerts its anti-tumor effects by downregulating SPC24 post-transcriptionally, thereby suppressing tumor growth and progression. Our findings elucidate a new molecular pathway through which dietary fiber protects against CRC and highlight LOH12CR2 as a potential therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112079"},"PeriodicalIF":3.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903513","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":"Poly-L-Arginine induces asthma pyroptosis in lung epithelial cells by promoting nuclear translocation of the PKM2 dimer","authors":"Shuang Chang ,&nbsp;Xiaoxia Feng ,&nbsp;Xu Chen ,&nbsp;Min Pan ,&nbsp;Xueqin Jiang ,&nbsp;Zhangyan Ke ,&nbsp;Xingyu Yang ,&nbsp;Minglong Guan ,&nbsp;Xiaojun Zha ,&nbsp;Lingling Zhang ,&nbsp;Xiaoyun Fan","doi":"10.1016/j.cellsig.2025.112066","DOIUrl":"10.1016/j.cellsig.2025.112066","url":null,"abstract":"<div><div>Inflammation is a principal mechanism in asthma pathogenesis. Activated eosinophils (EOSs) play an important role in the chronic inflammatory environment of asthma by releasing major basic protein (MBP) and other cationic granule proteins. Pyroptosis has been demonstrated to participate in asthma-related inflammation. Recent studies have reported the involvement of Pyruvate kinase M2 (<em>PKM2</em>) in inflammation development, but its precise mechanism remains elusive. In this study, the levels of <em>PKM2</em> and nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (<em>NLRP3</em>) messenger ribonucleic acids (mRNAs) in peripheral blood were observed to have a positive correlation with the eosinophil count in clinical samples from asthma patients. In addition, pyroptosis was detected in not only a chronic asthma mouse model induced by Ovalbumin (OVA) but also lung epithelial cell lines treated with Poly-L-arginine (PLA), which is a mimic of MBP. Subsequent TEPP-46 (a <em>PKM2</em> activator) treatment contributed to the alleviation of pyroptosis. PLA up-regulated the expression of <em>PKM2</em> and promoted the translocation of <em>PKM2</em> dimers to the nucleus of lung epithelial cells. Therefore, it was hypothesized that targeting the regulation of <em>PKM2</em> dimer nuclear translocation to reduce pyroptosis may provide innovative therapeutic principles for asthma. After treatment of cells with rapamycin, an inhibitor of <em>mTORC1</em>, inhibition of <em>mTORC1</em> resulted in a decrease in PLA-induced <em>PKM2</em> expression. Therefore, we hypothesize that reducing pyrodeath by regulating <em>PKM2</em> dimer nuclear translocation may provide an innovative therapeutic principle for the treatment of asthma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112066"},"PeriodicalIF":3.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944875","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":"CBX2 and EZH2 cooperatively contribute to 5-Fu resistance in gastric cancer by suppressing ferroptosis via trimethylation of H3k27","authors":"Miaomiao Zeng ,&nbsp;Bangxue Li ,&nbsp;Quanlin Guan ,&nbsp;Hui Cai","doi":"10.1016/j.cellsig.2025.112078","DOIUrl":"10.1016/j.cellsig.2025.112078","url":null,"abstract":"<div><h3>Background and objective</h3><div>Chromobox 2 (CBX2) plays a pivotal role in the malignant phenotypes of several cancers, which has been found to up-regulated in gastric cancer (GC). This study aimed to investigate the specific function and underlying mechanism of CBX2 in GC.</div></div><div><h3>Methods</h3><div>The potential role of CBX2 in GC was uncovered based on online bioinformatic analysis. The protein and mRNA expression levels were assessed by immunohistochemistry, qRT-PCR, and western blot. Using parental and the corresponding resistant GC cell lines, the effect and mechanism of CBX2 on 5-Fu resistance were explored by cell transfection technique, CCK-8 kit, colony formation assay, flow cytometry, the commercial kit, as well as co-IP. Xenograft tumor nude mice models were applied for in vivo assay.</div></div><div><h3>Results</h3><div>The expression of CBX2 was up-regulated in tumor tissues of GC patients and positively correlated with chemo-resistance, as well as that of EZH2. Knockdown of CBX2 resensitized 5-Fu resistant GC cells to 5-Fu while overexpressing CBX2 enhance GC cells against 5-Fu via the regulation of ferroptosis. In vivo experiments demonstrated that CBX2 overexpression enhanced 5-Fu sensitivity in tumors. Mechanically, CBX2 and EZH2 cooperatively suppressed ferroptosis in GC cells by inducing trimethylation of H3k27 (H3k27me3). Suppressing EZH2 blocked the inductive effect of CBX2 overexpression on 5-FU sensitivity of GC cells and reduced ferroptosis and H3k27me3 levels in CBX2 overexpressed GC cells.</div></div><div><h3>Conclusion</h3><div>CBX2/EZH2 cooperatively confers 5-FU resistance in GC cells through suppressing ferroptosis via H3k27me3, which may lead to a promising therapeutic strategy for GC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112078"},"PeriodicalIF":3.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944824","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":"GPR55 activation alleviates cognitive dysfunction caused by neuropathic pain through modulation of microglia polarization and synaptic plasticity via the CaMKKβ/AMPK/SOCS3 signaling pathway","authors":"Fengtian Zhao ,&nbsp;Xiaoyu Zhang ,&nbsp;Ting Liu ,&nbsp;Jiale Sun ,&nbsp;Xiaoqiang Li ,&nbsp;Wen Zhang ,&nbsp;Xuebi Tian","doi":"10.1016/j.cellsig.2025.112070","DOIUrl":"10.1016/j.cellsig.2025.112070","url":null,"abstract":"<div><div>Cognitive impairment induced by neuropathic pain substantially diminishes quality of life, with hippocampal neuroinflammation identified as a critical pathogenic factor. Although G protein-coupled receptor 55 (GPR55) demonstrates anti-inflammatory, analgesic, and neuroprotective properties, its therapeutic potential and molecular mechanisms in neuropathic pain-induced cognitive deficits remain uncharacterized. Using a spared nerve injury (SNI) mouse model, we systematically investigated GPR55's neuroprotective mechanisms. Pharmacological activation of GPR55 effectively ameliorated cognitive dysfunction and attenuated hippocampal neuroinflammation and preserved synaptic plasticity by shifting microglial polarization toward the neuroprotective M2 phenotype in SNI mice. Mechanistic studies revealed that the immunomodulatory effects operate through the CaMKKβ/AMPK/SOCS3 signaling axis, as confirmed by pathway blockade using the specific inhibitor Compound C. These results demonstrate that GPR55 activation modulates microglial polarization, mitigates neuroinflammatory cascades, and preserves synaptic plasticity, thus alleviating neuropathic pain-associated cognitive dysfunction through a mechanism involving the CaMKKβ/AMPK/SOCS3 signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112070"},"PeriodicalIF":3.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892102","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":"ABLIM1 promotes the proliferation, migration and invasion of osteosarcoma through DCC mediated activation of PI3K/AKT signaling pathway","authors":"Qi Liao ,&nbsp;Siqi Tong ,&nbsp;Lan Li ,&nbsp;Jianjian Wang ,&nbsp;Kai Tong","doi":"10.1016/j.cellsig.2025.112077","DOIUrl":"10.1016/j.cellsig.2025.112077","url":null,"abstract":"<div><h3>Background</h3><div>Actin-binding LIM protein 1 (ABLIM1) is a member of the LIM domain protein family and has been identified as a novel E3 ubiquitin ligase. However, its precise biological function remains incompletely characterized. This study aimed to investigate the role of ABLIM1 in modulating the biological behavior of osteosarcoma cells and elucidate the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>Through integrated bioinformatic analyses and experimental validation, we characterized ABLIM1 dysregulation in osteosarcoma and evaluated its prognostic significance. To determine ABLIM1's impact on osteosarcoma cell proliferation, migration, and invasion, we conducted comprehensive in vitro functional assays including CCK-8, EdU incorporation, wound healing, and Transwell invasion analyses. Subsequent investigation of ABLIM1-associated downstream pathways employed Western blotting and metabolic profiling, followed by rigorous validation experiments. Finally, we established a subcutaneous xenograft tumor model in nude mice to assess ABLIM1's in vivo functions.</div></div><div><h3>Results</h3><div>Silencing ABLIM1 significantly inhibited the proliferation, migration and invasion of osteosarcoma cells. On the contrary, overexpression of ABLIM1 resulted in the converse phenotype. In animal models, we injected silenced ABLIM1 143B osteosarcoma cells subcutaneously. The results showed that inhibiting the expression of ABLIM1 impaired the growth of osteosarcoma.</div></div><div><h3>Conclusion</h3><div>Our research results indicate that ABLIM1 may be an independent prognostic factor for individuals diagnosed with osteosarcoma. By regulating the DCC/PI3K/AKT/mTOR axis, ABLIM1 promotes the growth, migration and invasion of osteosarcoma cells. Therefore, targeting ABLIM1 may serve as an effective therapeutic target for the treatment of osteosarcoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112077"},"PeriodicalIF":3.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892104","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":"Hydrogen sulfide alleviates vascular smooth muscle cell senescence by inhibiting endoplasmic reticulum stress","authors":"Lijie Jiao ,&nbsp;Qiuyi Yan ,&nbsp;Jiahe Yang,&nbsp;Ren Wu,&nbsp;Ziyi Wei,&nbsp;Jiawen Ruan,&nbsp;Guoliang Yan,&nbsp;Xu Chen,&nbsp;Hongzhu Li","doi":"10.1016/j.cellsig.2025.112075","DOIUrl":"10.1016/j.cellsig.2025.112075","url":null,"abstract":"<div><div>The senescence of vascular smooth muscle cells (VSMCs) leads to the degeneration of vascular structure and function, as well as age-related cardiovascular diseases. Hydrogen sulfide (H₂S) has been proven to suppress the progression of various cardiovascular diseases by decreasing endoplasmic reticulum (ER) stress, but it remains unclear whether it can inhibit ER stress to alleviate the senescence of VSMCs. In the present study, the results of cell experiments showed that 10 g/L D-galactose (D-gal) increased the VSMCs senescence, oxidative stress, the expression of ER stress related proteins (GRP78, CHOP) and up-regulated pathways of IRE1-XBP1, PERK-eIF-2 α-ATF4 and ATF6 as well as decreased the expression of the cystathionine gamma-lyase (CSE) and H₂S production. H₂S supplement significantly reversed the effect of D-gal on the above indicators. Meanwhile, we also observed similar results in vascular tissues of naturally aged mice. In addition, naturally aged mice exhibited reduction of vascular elastic fibers and accumulation of collagen fibers as well as thickening of the vascular wall, while supplementation with H₂S was able to alleviate these phenomena. At the same time, we also found that H₂S could restore the S-sulfhydration level of GRP78. The knockdown and the Cys42 mutation in GRP78 completely abrogated H₂S-mediated suppression of VSMCs senescence by decreasing ER stress. Our results suggest that H₂S can delay the senescence of VSMCs by decreasing ER stress by down-regulating IRE1-XBP1, PERK-eIF-2α-ATF4 and ATF6 pathways via increasing the S-sulfhydration level of GRP78 by the Cys42 site.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112075"},"PeriodicalIF":3.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892045","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":"Hypoxia-induced HIF1A impairs sorafenib sensitivity in hepatocellular carcinoma through NSUN2-mediated stabilization of GDF15","authors":"Lude Wang ,&nbsp;Bo Zhuang ,&nbsp;Yiwen Jiang ,&nbsp;Zewei Chen ,&nbsp;Chenyang Ge ,&nbsp;Min Yu ,&nbsp;Shian Yu ,&nbsp;Haiping Lin","doi":"10.1016/j.cellsig.2025.112076","DOIUrl":"10.1016/j.cellsig.2025.112076","url":null,"abstract":"<div><h3>Background</h3><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Although sorafenib is a first-line systemic therapy for advanced HCC, resistance to treatment remains a major challenge. Hypoxia is a hallmark of the tumor microenvironment and is known to promote tumor growth and progression; however, its role in modulating sorafenib response in HCC remains poorly understood.</div></div><div><h3>Methods</h3><div>HCC cell lines (Hep3B and Huh7) were cultured under normoxic or hypoxic conditions and treated with sorafenib. Cell viability, apoptosis, and colony formation assays were conducted to evaluate the effect of hypoxia on sorafenib sensitivity. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to confirm HIF1A-mediated transcriptional regulation. RNA sequencing, m5C-RIP-Seq, and bioinformatics analysis were performed to identify NSUN2-mediated downstream targets. The therapeutic efficacy of GDF15 neutralization in combination with sorafenib was assessed both in vitro and in vivo.</div></div><div><h3>Results</h3><div>Hypoxia significantly reduced HCC cell sensitivity to sorafenib, as evidenced by increased IC50 values and decreased apoptosis. Mechanistically, hypoxia-induced HIF1A upregulated the RNA m5C methyltransferase NSUN2, which stabilized GDF15 mRNA through m5C modification, leading to enhanced GDF15 secretion. Neutralization of GDF15 inhibited Akt/mTOR signaling and enhanced sensitivity to sorafenib in both in vitro and in vivo models.</div></div><div><h3>Conclusion</h3><div>This study uncovers a novel mechanism by which hypoxia-induced HIF1A promotes sorafenib resistance in HCC via the NSUN2-mediated stabilization and upregulation of GDF15. Targeting the HIF1A/NSUN2/GDF15 axis offers a promising therapeutic strategy to overcome sorafenib resistance in HCC patients.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112076"},"PeriodicalIF":3.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892103","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":"LncRNA LINC00667 inhibits breast cancer progression by regulating POTEE to suppress mitochondrial oxidative phosphorylation.","authors":"Zhengling Yu ,&nbsp;Keying Xu ,&nbsp;Yini Shang ,&nbsp;Changhui Geng ,&nbsp;Youxue Zhang ,&nbsp;Lihong Wang","doi":"10.1016/j.cellsig.2025.112074","DOIUrl":"10.1016/j.cellsig.2025.112074","url":null,"abstract":"<div><div>Breast cancer (BC) is characterized by significant heterogeneity, which is reflected in genetic mutations and aberrant protein expression. Although long noncoding RNAs (lncRNAs) are known to influence the progression of BC, their regulatory roles in posttranslational modifications remain poorly understood. In this study, we investigated the function of <em>LINC00667</em>, an intergenic lncRNA that is downregulated in BC cell lines and tissues. Our results demonstrate that <em>LINC00667</em> serves as a favorable prognostic marker for breast cancer. Functional characterization revealed that overexpression of <em>LINC00667</em> suppresses malignant progression, while its knockdown promotes oncogenic phenotypes in BC. Mechanistically, we used CHIRP and RIP assays to confirm direct binding interactions between <em>LINC00667</em> and two proteins: ubiquitin B (UBB) and POTE ankyrin domain family member E (POTEE). We found that <em>LINC00667</em> reduces POTEE expression and inhibits mitochondrial oxidative phosphorylation (OXPHOS). Specifically, silencing of POTEE decreased the expression of OXPHOS complexes, an effect that could be rescued by knockdown of <em>LINC00667</em>. Conversely, overexpression of POTEE enhanced OXPHOS activity, which was counteracted by overexpression of <em>LINC00667</em>. Cycloheximide (CHX) chase experiments revealed that <em>LINC00667</em> overexpression accelerated POTEE degradation, while treatment with the proteasome inhibitor MG132 stabilized POTEE levels. Furthermore, we identified TRIM33 as the E3 ligase responsible for mediating POTEE ubiquitination. Collectively, our findings demonstrate that <em>LINC00667</em> inhibits breast cancer progression by promoting TRIM33-mediated ubiquitination and subsequent degradation of POTEE, thereby regulating mitochondrial OXPHOS activity. These results highlight the critical role of <em>LINC00667</em> in the posttranslational regulation of protein stability and mitochondrial function in BC, and suggest that targeting the <em>LINC00667</em>-POTEE axis may represent a potential therapeutic strategy for this disease.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"135 ","pages":"Article 112074"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893285","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}