Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"RIPK3 activation promotes peritoneal dialysis-related peritoneal fibrosis via NLRP3/Caspase-1/IL-1β pathway","authors":"Zhiyong Xie ,&nbsp;Rong Wei ,&nbsp;Wenying Zhang ,&nbsp;Xiaodong Tang ,&nbsp;Hang Chen ,&nbsp;Qilan Nie ,&nbsp;Xinying Zhang ,&nbsp;Yilin Chen ,&nbsp;Zhuohan Li ,&nbsp;Ziqing Tan ,&nbsp;Minwei Du ,&nbsp;Yuyao Zhang ,&nbsp;Xuan Peng ,&nbsp;Hui Di ,&nbsp;Yueqiang Wen ,&nbsp;Ying Huang ,&nbsp;Long Xiao ,&nbsp;Jianbo Liang ,&nbsp;Dezhu Chen ,&nbsp;Zebin Wang ,&nbsp;Ying Zhang","doi":"10.1016/j.bbamcr.2025.120060","DOIUrl":"10.1016/j.bbamcr.2025.120060","url":null,"abstract":"<div><div>Peritoneal fibrosis is one of the leading causes for withdraw of peritoneal dialysis (PD) but there is no available effective therapy strategy. As an essential role in regulating TNF-induced necroptosis, receptor interacting protein kinase-3 (RIPK3) participated in the progression of multiple organ fibrosis. Here, we investigated the role and the possible mechanism of RIPK3 in PD-associated peritoneal fibrosis in PD patients, a mouse peritoneal dialysis model and in vitro peritoneal mesothelial cells. We found that phosphorylated-RIPK3 (p-RIPK3) were markedly elevated in PD fluids and peritoneal tissue from PD patients, a mouse PD model and in peritoneal mesothelial cells induced by TGFβ and high glucose PD fluids. And activated RIPK3 recruits its substrate protein, MLKL, and promotes its phosphorylation. RIPK3 kinase inhibition using GSK’872 compound could attenuate high glucose PD fluid-induced peritoneal fibrosis in a mouse PD model. In vitro peritoneal mesothelial cells, RIPK3 kinase inhibition or siRNA transfection target on RIPK3 attenuate TGFβ or high glucose PD fluid-induced fibrotic progress. Meanwhile, GSK’872 intervention could inhibit the NLRP3/Caspase-1/IL-1β pathway in PD mouse model and in vitro peritoneal mesothelial cells, inhibiting RIPK3 kinase activity or siRNA silencing RIPK3 expression could block NLRP3/Caspase-1/IL-1β pathway. Moreover, Co-immunoprecipitation (Co-IP) experiment and immunofluorescence indicated that p-RIPK3 could combinate with NLRP3 and TGFβ intervention could promote this interaction, while RIPK3 kinase inhibitor could avianize their combination. These findings implicate that RIPK3 activation may be a crucial mediator in PD associated peritoneal fibrosis and targeting RIPK3 activation may be a novel therapeutic strategy to attenuate PD-related peritoneal fibrosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120060"},"PeriodicalIF":3.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069039","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":"2025-09-08","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":"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":"2025-09-07","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":"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":"2025-09-05","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":"TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy","authors":"Pandian Nagakannan ,&nbsp;Md Imamul Islam ,&nbsp;Shakila Sultana ,&nbsp;Soheila Karimi-Abdolrezaee ,&nbsp;Eftekhar Eftekharpour","doi":"10.1016/j.bbamcr.2025.120054","DOIUrl":"10.1016/j.bbamcr.2025.120054","url":null,"abstract":"<div><div>Ferroptosis is a recently discovered lytic form of cell death that is triggered by iron-driven excessive lipid peroxidation and depletion of glutathione and glutathione peroxidase-4 (GPX4). This form of cell death has been linked to a wide range of conditions from cancer to neurodegenerative diseases. Using murine hippocampal HT22 neurons, we aimed to investigate the underlying mechanisms of glutamate-mediated ferroptosis. A robust increase in Thioredoxin-Inhibiting Protein (TXNIP) prompted us to use genetic approaches and examine the role of this protein in ferroptosis in HT22 neurons, mouse embryonic fibroblasts, and Hela cells. Our results indicate that TXNIP is a key player in ferroptotic pathway, as its deletion conferred resistance to classic ferroptosis-inducing agents (erastin, RSL3, and ML210), while TXNIP overexpression increased their susceptibility to ferroptosis. Notably, TXNIP deletion protected cells from mitochondrial dysfunction induced by ferroptotic agents, independent of GSH and GPX4 levels. We further showed that TXNIP mediates ferroptosis through facilitating degradation of the iron-binding protein ferritin via NCOA4-mediated ferritinophagy. This resulted in elevated cytosolic labile iron levels, therefore amplifying lipid peroxidation, and promoting ferroptosis. Our findings suggest that TXNIP acts as a positive regulator of ferroptosis by modulating autophagy and iron availability. Targeting TXNIP might hold promise in developing drugs for diseases involving the ferroptotic pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120054"},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008201","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":"NRAMP family in plants: Contribution to cadmium accumulation","authors":"Katarzyna Kozak ,&nbsp;Danuta Maria Antosiewicz","doi":"10.1016/j.bbamcr.2025.120056","DOIUrl":"10.1016/j.bbamcr.2025.120056","url":null,"abstract":"<div><div>The Natural Resistance Associated Macrophage Proteins (NRAMPs) are membrane-targeted transporters with low substrate specificity, that mediate the import (translocation to the cytoplasm) of metals, mainly essential nutrients, e.g. iron (Fe), manganese (Mn), zinc (Zn), cobalt (Co), copper (Cu) or nickel (Ni). Depending on the subcellular localisation, they contribute to either uptake or redistribution. Numerous studies have shown that NRAMP proteins also mediate the transport of non-essential toxic metals, and constitute the major pathway for the uptake of cadmium (Cd) in plants. Given the threat to living organisms from exposure to this toxic metal, which enters the food chain through edible plant parts, this review focuses on how different NRAMP proteins are involved in Cd uptake and accumulation. The issue was discussed concerning three categories of plants: (i) the model plant <em>Arabidopsis thaliana</em>; (ii) crop plants that are mainly used for food; (iii) plant species used for the phytoremediation of Cd-polluted environments, including hyperaccumulators. For the sake of clarity, this paper updates the structure, function and regulation of <em>NRAMP</em> genes and proteins, their phylogenetic relationships, and their substrates, filling a knowledge gap, and discussing these topics in light of new data. Furthermore, this review discusses the potential applications of <em>NRAMP</em> genes in plant biotechnology, such as generating low-Cd food and phytoremediation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 1","pages":"Article 120056"},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008167","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":"S100A16 knockdown reduces RPN2 expression and inhibits β-catenin/TCF signaling, leading to suppressed metastasis in cervical cancer cells","authors":"Min-Chieh Hsin ,&nbsp;Po-Hui Wang ,&nbsp;Pei-Ni Chen ,&nbsp;Yi-Hsien Hsieh ,&nbsp;Shun-Fa Yang ,&nbsp;Chung-Yuan Lee","doi":"10.1016/j.bbamcr.2025.120053","DOIUrl":"10.1016/j.bbamcr.2025.120053","url":null,"abstract":"<div><div>S100 calcium-binding protein A16 (S100A16), the most recently identified member of the S100 calcium-binding protein family, has been implicated in various cancers. However, its specific role in cervical cancer remains unclear. In this study, we demonstrated that silencing the S100A16 gene inhibits the migratory ability of HeLa and SiHa cells without affecting their viability. RNA sequencing analysis revealed that S100A16 significantly regulates ribophorin II (RPN2). Furthermore, RPN2 knockdown alone effectively suppressed cell migration and overexpression of S100A16 reversed the inhibition of migration caused by RPN2 silencing. Mechanistically, S100A16 was observed to regulate RPN2 through phosphorylated signal transducer and activator of transcription 3 (p-STAT3), which, in turn, modulated the downstream β-catenin/TCF pathway via phosphorylated GSK3β. An analysis of nuclear and cytosolic protein fractions further indicated that S100A16 silencing reduces the ability of β-catenin to translocate into the nucleus. In conclusion, our research revealed that S100A16 silencing downregulated RPN2 levels through p-STAT3, thereby inhibiting the p-GSK3β/β-catenin/TCF signaling pathway. These findings highlight S100A16 as a potential therapeutic target for cervical cancer.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120053"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988545","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":"Corrigendum to \"Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina\" [Biochim. Biophys. Acta (BBA) Mol. Cell Res. 1867 (2020) 118732 10.1016/j.bbamcr.2020.118732].","authors":"Marcelo Cossenza, Renato Socodato, Telmo A Mejía-García, Ivan Domith, Camila C Portugal, Luis F H Gladulich, Aline T Duarte-Silva, Latika Khatri, Shannon Antoine, Franz Hofmann, Edward B Ziff, Roberto Paes-de-Carvalho","doi":"10.1016/j.bbamcr.2025.120050","DOIUrl":"10.1016/j.bbamcr.2025.120050","url":null,"abstract":"","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":" ","pages":"120050"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940769","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":"2025-08-30","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":"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":"2025-08-27","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}