Cellular signalling最新文献

{"title":"Hypoxia ameliorates high-fat-diet-induced hepatic lipid accumulation by modulating the HIF2α/PP4C signaling","authors":"Zhe Liu ,&nbsp;Jing Hou ,&nbsp;MeiYuan Tian ,&nbsp;YaoGang Zhang ,&nbsp;DengLiang Huang ,&nbsp;Na Zhao ,&nbsp;Yanyan Ma ,&nbsp;Sen Cui","doi":"10.1016/j.cellsig.2025.111751","DOIUrl":"10.1016/j.cellsig.2025.111751","url":null,"abstract":"<div><div>Hepatic lipid accumulation is a hallmark of metabolically associated fatty liver disease (MAFLD), which contributes to the progression of cirrhosis and even hepatoma. However, the underlying mechanisms remain poorly understood. Protein phosphatase 4C (PP4C) is an important enzyme that exists widely in the body and participates in cell metabolism. Hypoxia can affect the development of metabolic diseases. In this study, we investigated the role of PP4C in hepatic lipid metabolism under hypoxia in vivo and in vitro. Hypoxia-inducible factor 2α (HIF2α), PP4C, phosphorylated AU-rich element RNA-binding factor 1(pAUF1), acetyl-CoA carboxylase 1 (ACC1), and carnitine palmitoyl transferase-1 (CPT1) were analyzed via western blotting and immunofluorescence. The mechanism by which PP4C affects hepatic lipid accumulation under hypoxia was evaluated in stable transfected cell lines. Compared with those in the 2200 m HFD group, body weight, triglyceride (TG), total cholesterol (TC), amino alanine transferase (ALT), aspartate transaminase (AST), and lipid accumulation were lower in the 4500 m HFD group (<em>P</em> &lt; 0.05). Compared with those in the 4500 m ND group, ACC1 and PP4C levels were lower than in the 4500 m HFD group, but HIF2α, pAUF1, and CPT1 levels were greater (<em>P</em> &lt; 0.05). Knockdown of <em>HIF2α</em> prevented the hypoxia-induced reduction of PP4C, confirming the regulatory role of the HIF2α-PP4C axis in hepatic lipid metabolism. PP4C could affect the phosphorylation and expression localization of AU-rich element RNA-binding factor 1 (AUF1). PP4C enhanced lipid accumulation by reducing pAUF1, while the knockdown of <em>PP4C</em> had the opposite effect; pAUF1 had no change. Compared with those in the control group, ACC1 levels were decreased and CPT1 levels were increased in the <em>AUF1</em> overexpression group, whereas ACC1 and CPT1 levels were not altered in the <em>AUF1</em> knockdown group (<em>P</em> &lt; 0.05). In conclusion, hypoxia might improve lipid accumulation by downregulating PP4C via HIF2a. PP4C is involved in hepatic lipid metabolism by regulating AUF1 phosphorylation under different oxygen concentrations. PP4C might be a promising target for treating hepatic lipid accumulation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111751"},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669122","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":"Rosuvastatin inhibits carcinogenesis through Ca2+ triggered endoplasmic reticulum stress pathway in pancreatic cancer","authors":"Hui Miao ,&nbsp;Baojian Zhang ,&nbsp;Yue Li ,&nbsp;Xiao Ma ,&nbsp;Yang Yang ,&nbsp;Zhenhua Lin ,&nbsp;Yanqun Liu","doi":"10.1016/j.cellsig.2025.111753","DOIUrl":"10.1016/j.cellsig.2025.111753","url":null,"abstract":"<div><h3>Background</h3><div>Pancreatic cancer remains one of the most challenging malignancies to treat due to its late-stage diagnosis, aggressive progression, and high resistance to existing therapies. Rosuvastatin (ROV), known for its hypolipidemic effects, which significantly inhibited clonogenic capacity and epithelial-mesenchymal transition (EMT) in prostate cancer cells. However, the anti-cancer mechanisms of ROV in PC have not yet been fully explored.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the potential anti-cancer effects of ROV on PC cells and to elucidate the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Cytotoxicity was detected <em>via</em> MTT assay, while epithelial-mesenchymal transition (EMT) markers, Ca²⁺ levels, and endoplasmic reticulum (ER) stress were observed with fluorescence microscopy. RNA-seq analysis was used to identify significantly changed mRNA expression following ROV treatment. Additionally, western blotting and immunohistochemistry (IHC) were conducted to examine proteins involving in the cell cycle, EMT, Ca²⁺ signaling, and endoplasmic reticulum stress (ERS) <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Results</h3><div>ROV inhibited PC cell proliferation by arresting the cell cycle at the G1/S phase and partially reducing cell mobility during the EMT process. A total of 1336 significantly different RNAs (<em>P</em> &lt; 0.05 and |logFC|&gt;1) were identified and analyzed through RNA-seq, revealing the Ca²⁺ and ER pathways in PC cells treated with ROV. ROV treatment significantly altered the level of intracellular Ca²⁺, triggering the ERS pathway and modulating the Ca²⁺/CaM/CaMKII/ERK pathway. Furthermore, ROV inhibited key proteins within the Ca²⁺ and ERS pathways, leading to reduced cell proliferation, mobility and G1/S phase arrest. In tumor tissues, the expression of Ki67, EMT markers, Calmodulin, and ATF6 corroborated the <em>in vitro</em> findings.</div></div><div><h3>Conclusion</h3><div>ROV inhibited proliferation and metastasis in PC cells by inhibiting the EMT process through the Ca²⁺/CaM/CaMKII/ERK and Ca²⁺-mediated ERS pathways, highlighting its potential as a prophylactic and therapeutic agent for PC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111753"},"PeriodicalIF":4.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662799","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":"Synergic effect of the combination of isoliquiritigenin and arsenic trioxide in HepG2 liver cancer cells","authors":"Jingjing Li ,&nbsp;Juan Gu ,&nbsp;Sijia Pan ,&nbsp;Nuo Deng ,&nbsp;Muhammad Khan ,&nbsp;Lingyan Li ,&nbsp;Xiao Wu ,&nbsp;Yongming Li","doi":"10.1016/j.cellsig.2025.111752","DOIUrl":"10.1016/j.cellsig.2025.111752","url":null,"abstract":"<div><div>Despite continuous therapeutic interventions, the prognosis of hepatocellular carcinoma (HCC) remains very poor. Thus, quest for novel treatment strategies to improve therapeutic window of HCC therapy is paramount. Arsenic trioxide (ATO) is commonly used as the first-line treatment for acute promyelocytic leukemia (APL). Isoliquiritigenin (ISL) is a potential plant-based bioactive molecule with versatile biological and pharmacological effects including anticancer effect.</div><div>The present study aimed to investigate the potential synergistic effects of combination of ISL and ATO in HCC cells. The data revealed that the combination of ISL and ATO synergistically inhibited HCC cell proliferation. The collective data demonstrate that synergistic anticancer effect of combined treatment of ISL + ATO was achieved <em>via</em> cooperative induction of mitochondrial apoptosis through ROS generation and inhibition of PI3K/Akt/mTOR pathway. In addition, ROS generation and suppression of PI3K/Akt/mTOR pathway were found to be two independent events in induction of apoptosis. Finally, we observed that combination treatment effectively suppressed tumor growth in nude mice xenograft model through induction of intrinsic apoptosis and inhibition of PI3K/Akt/mTOR pathway.</div><div>In conclusion, the findings of this study suggest that both drugs work synergistically to exert anti-tumor effect in HCC, both <em>in-vitro</em> and <em>in-vivo</em> and could offer novel strategy for liver cancer treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111752"},"PeriodicalIF":4.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662811","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":"Decoding intricate interactions between m6A modification with mRNAs and non-coding RNAs in cervical cancer: Molecular mechanisms and clinical implications","authors":"Xuefei Liu ,&nbsp;Lizhi Zhang ,&nbsp;Ji Chen ,&nbsp;Wei Shao","doi":"10.1016/j.cellsig.2025.111745","DOIUrl":"10.1016/j.cellsig.2025.111745","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) methylation is the most prevalent RNA modification that is regulated by three regulatory factors: “writers”, “erasers” and “readers”. m6A modification regulates RNA stability and other mechanisms, including translation, cleavage, and degradation. Current research has demonstrated that m6A methylation is involved in the regulation of occurrence and development of cancers by controlling the expression of cancer-related genes. This review summarizes the role of m6A modification on messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) in cervical cancer (CC). We highlight the dual role of m6A regulatory factors, which act as oncogenes or tumor suppressors depending on the cellular context and downstream targets. Additionally, we examine how ncRNAs reciprocally regulate m6A modification in two ways: by guiding the deposition or removal of m6A modifications on RNA targets, and by modulating the expression of m6A regulatory factors. These interactions further contribute to tumor progression. Furthermore, the therapeutic potential of targeting m6A modification has been emphasized in CC. Moreover, recent advances in small-molecule inhibitors targeting m6A regulators and RNA-based therapies which may offer new treatment strategies have been summarized. Finally, we discuss the current challenges in m6A modification research and provide suggestions for future research directions. This review aims to deepen the understanding of m6A modification in CC and contribute to the development of targeted and personalized treatment strategies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111745"},"PeriodicalIF":4.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643933","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":"Unravelling the epigenetic based mechanism in discovery of anticancer phytomedicine: Evidence based studies","authors":"Bushra Bashir ,&nbsp;Pranshul Sethi ,&nbsp;Satyajit Panda ,&nbsp;Hemanth Kumar Manikyam ,&nbsp;Sukriti Vishwas ,&nbsp;Sachin Kumar Singh ,&nbsp;Kuldeep Singh ,&nbsp;Divya Jain ,&nbsp;M.V.N.L. Chaitanya ,&nbsp;Henrique Douglas Melo Coutinho","doi":"10.1016/j.cellsig.2025.111743","DOIUrl":"10.1016/j.cellsig.2025.111743","url":null,"abstract":"<div><div>Epigenetic mechanisms play a crucial role in the normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of these processes can result in changes to gene function and the transformation of cells into a malignant state. Cancer is characterized by widespread alterations in the epigenetic landscape, revealing that it involves not only genetic mutations but also epigenetic abnormalities. Recent progress in the field of cancer epigenetics has demonstrated significant reprogramming of various components of the epigenetic machinery in cancer, such as DNA methylation, modifications to histones, positioning of nucleosomes, and the expression of non-coding RNAs, particularly microRNAs. The ability to reverse epigenetic abnormalities has given rise to the hopeful field of epigenetic therapy, which has shown advancement with the recent approval by the FDA of three drugs targeting epigenetic mechanisms for the treatment of cancer. In the present manuscript, a comprehensive review has been presented about the role of understanding the epigenetic link between cancer and mechanisms by which phytomedicine offers treatment avenues. Further, this review deciphers the significance of natural products in the identification of epigenetic therapeutics, the diversity of their molecular targets, the use of nanotechnology, and the creation of new strategies for overcoming the inherent clinical challenges associated with developing these drug leads.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111743"},"PeriodicalIF":4.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662815","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":"TAK-901, a novel EPHA2 inhibitor as a therapeutic strategy against prostate cancer","authors":"Shanhui Liu ,&nbsp;Shengjun Fu ,&nbsp;Xuewu Wu ,&nbsp;Shan Wu ,&nbsp;Youli Zhao ,&nbsp;Xinyue Wu ,&nbsp;Liting Yan ,&nbsp;Jianzhong Lu ,&nbsp;Lanlan Li ,&nbsp;Yan Tao","doi":"10.1016/j.cellsig.2025.111750","DOIUrl":"10.1016/j.cellsig.2025.111750","url":null,"abstract":"<div><div>Prostate cancer is the most common cancer and remains a leading cause of cancer-related deaths among men worldwide. Androgen deprivation therapy continues to be the cornerstone of treatment for prostate cancer. However, the efficacy of this treatments is often limited, leading to the emergence of drug resistance and tumor recurrence. TAK-901, an inhibitor of Aurora kinase B, has been shown to inhibit tumor growth both in vitro and in vivo models. To date, the effect of TAK-901 on prostate cancer and the underlying mechanism remain unknown. In this study, we found that TAK-901 could inhibit proliferation, colony formation and migration, while also inducing apoptosis in prostate cancer cells. We further demonstrated that TAK-901 activates the CHK1 signaling pathway, leading to G2/M-phase arrest in these cells. Additionally, we identified EPHA2 as a novel therapeutic target of TAK-901. By mutating the binding sites between EPHA2 and TAK-901, we discovered that these mutations could reverse the anti-proliferative effects of TAK-901 in prostate cancer models. Our study is the first to reveal that TAK-901 induces apoptosis in prostate cancer cells and inhibits cell growth by targeting EPHA2. These findings provide valuable insights into the underlying mechanisms of TAK-901 and may develop its therapeutic applications in prostate cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111750"},"PeriodicalIF":4.4,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of toll-like receptor 2 promotes the expression of inflammatory mediators and cell proliferation of human polycystic kidney disease cells","authors":"Yang Zhang ,&nbsp;Matthew Plansinis ,&nbsp;Sophia Peak ,&nbsp;Elisabeth Weber ,&nbsp;Aiping Wei ,&nbsp;Yu Xu ,&nbsp;Madelyn Ross ,&nbsp;Abigail Leagjeld ,&nbsp;Darren P. Wallace ,&nbsp;Yan Zhang","doi":"10.1016/j.cellsig.2025.111749","DOIUrl":"10.1016/j.cellsig.2025.111749","url":null,"abstract":"<div><div>Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive enlargement of fluid-filled cysts, leading to a decline in renal function. Toll-like receptors (TLR)-2 and TLR4 are pattern recognition receptors and components of the innate immune response. We found that mRNA levels for TLR2 and TLR4, an adaptor protein MyD88, and the transcription factor NF-κB were elevated in the kidneys of ADPKD patients and PKD mice. There was decreased expression of IκBα, an inhibitory protein sequestering NF-κB in the cytosol, and increased NF-κB nuclear translocation in human ADPKD kidneys compared with normal human kidneys (NHK). Pam3CSK4, a synthetic TLR2 agonist, increased the phosphorylation of IκBα, decreased its total levels, and caused NF-κB nuclear translocation and upregulation of pro-inflammatory mediators in cultured human ADPKD cells. Pam3CSK4 also increased phosphorylated ERK, a mitogen-activated protein kinase, and phosphorylated S6, a downstream target of the mTOR pathway, and accelerated ADPKD cell proliferation. By contrast, Pam3CSK4 did not affect NF-κB or ERK in NHK cells, but rather induced cytotoxicity, suggesting that TLR2 activation's effect was specific to ADPKD cells. Treatment with a TLR4 agonist did not affect NF-κB or ERK signaling in either ADPKD or NHK cells. Inhibition of TGF-β-activated kinase-1 (TAK1) effectively suppressed Pam3CSK4-induced NF-κB and ERK activation and the proliferation of ADPKD cells. These findings suggest that activation of TLR2 increases NF-κB-mediated-inflammatory mediators and ERK-dependent cell proliferation through TAK1 in ADPKD cells. We propose that the TLR2/TAK1 axis is a potential therapeutic target to reduce inflammation and cyst growth in ADPKD.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111749"},"PeriodicalIF":4.4,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the molecular mechanisms through which overexpression of TET3 alleviates liver fibrosis in mice via ferroptosis in hepatic stellate cells","authors":"Yin Liu ,&nbsp;Lin-Lin Feng ,&nbsp;Bing Han ,&nbsp;Li-Jun Cai ,&nbsp;Ran-Yang Liu ,&nbsp;Shuang Tang ,&nbsp;Qin Yang","doi":"10.1016/j.cellsig.2025.111747","DOIUrl":"10.1016/j.cellsig.2025.111747","url":null,"abstract":"<div><div>Hepatic stellate cell (HSC) activation is crucial in the onset and progression of liver fibrosis, and inhibiting or eliminating activated HSCs is a key therapeutic strategy. Ferroptosis may help eliminate activated HSCs; however, its role and regulatory pathways in liver fibrosis remain unclear. As a DNA demethylase, TET3 regulates gene expression via DNA demethylation. We previously demonstrated that TET3 overexpression alleviates CCL₄-induced liver fibrosis in mice; however, the specific mechanisms, including whether TET3 affects ferroptosis in HSCs, remain unexplored. Thus, we aimed to explore the molecular mechanisms wherein TET3 overexpression improves liver fibrosis in mice via ferroptosis in HSCs. Our in vivo observations showed that overexpression of TET3 ameliorate liver fibrosis in mice, and is associated with increased levels of malondialdehyde (MDA) and Fe²⁺ in liver tissue, as well as decreased protein expression of SLC7A11, GPX4, and FTH1. Further in vitro studies on HSCs showed that TET3 overexpression inhibits the expression of SLC7A11, GPX4, and FTH1, and reduces intracellular GSH levels, leading to accumulation of MDA and iron ions. This induces ferroptosis in HSC-LX2 cells, while simultaneously decreasing ECM accumulation in HSCs. Furthermore, hMeDIP-SEQ and ChIP-qPCR analyses revealed that TET3 directly interacts with the promoter regions of GPX4 and FTH1 to regulate their transcriptional expression. We propose that overexpression of TET3 modulates the gene methylation status of ferroptosis-related proteins, thereby regulating HSC ferroptosis, reducing activated HSCs, and decreasing ECM deposition in the liver. This may represent one of the molecular mechanisms wherein TET3 overexpression ameliorates liver fibrosis in mice.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111747"},"PeriodicalIF":4.4,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643931","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 AC100865.1 regulates macrophage adhesion and ox-LDL intake through miR-7/GDF5 pathway","authors":"Yong Ren ,&nbsp;Jiarong Liang ,&nbsp;Baofeng Chen ,&nbsp;Xiangyang Liu ,&nbsp;Jinfeng Chen ,&nbsp;Xiangying Liu ,&nbsp;Yunxian Chen","doi":"10.1016/j.cellsig.2025.111748","DOIUrl":"10.1016/j.cellsig.2025.111748","url":null,"abstract":"<div><h3>Objectives</h3><div>Cardiovascular disease (CVD) accounts for over 40 % of deaths related to diseases among residents. Atherosclerosis (AS) and its associated thrombosis are the primary causes of CVD. LncRNA AC100865.1, a newly identified lncRNA, has shown potential as a diagnostic biomarker for AS. This study aims to evaluate the therapeutic value of lncRNA AC100865.1 in AS.</div></div><div><h3>Methods</h3><div>Real-time PCR was conducted to assess the relative expression of lncRNA AC100865.1 in Peripheral Blood Mononuclear Cell (PBMC) samples from 50 CVD patients and 50 healthy controls. lncRNA AC100865.1 was overexpressed in RAW264.7 cells to measure its effects on adhesion and oxidized low-density lipoprotein (ox-LDL) uptake. Flow cytometry was utilized to identify the pathway mediating these processes. The luciferase assay and knockout rescue experiments were performed to elucidate the downstream signaling pathways involved.</div></div><div><h3>Results</h3><div>lncRNA AC100865.1 expression was found to be downregulated in CVD patients. Overexpression of lncRNA AC100865.1 significantly enhanced the adhesion capacity of RAW264.7 cells. Luciferase reporter assays and flow cytometry indicated that this effect is mediated through the miR-7/GDF5/p38/LFA-1 pathway. Furthermore, lncRNA AC100865.1 notably increased ox-LDL uptake by macrophages via upregulation of CD36 expression.</div></div><div><h3>Conclusion</h3><div>Overexpression of lncRNA AC100865.1 enhances the adhesion of RAW264.7 cells through the miR-7/GDF5/p38/LFA-1 pathway and increases ox-LDL uptake by elevating CD36 levels. These findings suggest that circulating lncRNA AC100865.1 may serve not only as an early diagnostic marker for CVD but also as a potential therapeutic target, offering new prospects for CVD treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111748"},"PeriodicalIF":4.4,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647496","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":"RORα inhibits proliferation and chemoresistance through AKR1A1-induced glucose and lipid reprogramming in gastric cancer","authors":"Xiaoshan Wang ,&nbsp;Mengding Chen ,&nbsp;Yuwei Wu ,&nbsp;Feixu Chen ,&nbsp;Tong Shen ,&nbsp;Zhengguang Wang","doi":"10.1016/j.cellsig.2025.111741","DOIUrl":"10.1016/j.cellsig.2025.111741","url":null,"abstract":"<div><h3>Background</h3><div>Abnormal glycolysis and lipid metabolism play important roles in the occurrence and development of gastric cancer (GC). Moreover, dysregulation of circadian genes is associated with metabolic reprogramming in the tumor microenvironment. This study aimed to determine the role of retinoic acid-related orphan receptor alpha (RORα) in glucose and lipid reprogramming in GC.</div></div><div><h3>Methods</h3><div>The effects on cell proliferation and chemoresistance in vitro and in vivo were studied using gain- and loss-of-function experiments. Glycolytic activity and lipid synthesis were assessed using a Seahorse assay and reagent kits. Moreover, the regulatory mechanisms were explored using half-life, coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), luciferase reporter and immunofluorescence colocalization assays in GC cells. In addition, the relationships of RORα with E47 and AKR1A1 were analyzed using public databases and retrospective clinicopathological analyses.</div></div><div><h3>Results</h3><div>RORα deletion promoted cell proliferation and fluorouracil (5-FU) chemoresistance by increasing glycolytic activity and lipid synthesis. In contrast, SR1078, an RORα activator, reversed these changes and had a synergistic inhibitory effect on cell proliferation in combination with 2-deoxygulose glucose (2-DG) or atorvastatin. Mechanistically, aldo-keto reductase family 1 member A1 (AKR1A1), is the key driver of RORα-mediated glucose and lipid reprogramming. Specifically, E47 is an AKR1A1 transcription factor, and its stability is affected by β-catenin. RORα deletion indirectly promoted E47 protein stability through the up-regulation of β-catenin, leading to increased AKR1A1 transcriptional activity. Moreover, RORα, E47 and AKR1A1 expression was dysregulated, and associated with clinicopathological parameters and prognosis in patients with GC. These expression patterns including RORα-low, E47-high and AKR1A1-high expression patterns alone or in combination were correlated with reduced responsiveness, poor prognosis, increased standard uptake value (SUV) levels and lipid droplet formation.</div></div><div><h3>Conclusions</h3><div>These findings reveal a novel mechanism by which RORα regulates glucose and lipid reprogramming and may be a promising target for GC treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111741"},"PeriodicalIF":4.4,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647499","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}