Cellular signalling最新文献

{"title":"Physical TRPV1-PKR2 interaction modulates PKR2 localization, activation and β-arrestin-2 recruitment","authors":"Rossella Miele ,&nbsp;Maria Rosaria Fullone ,&nbsp;Ida Casella ,&nbsp;Daniela Maftei ,&nbsp;Giorgio Prosperi ,&nbsp;Antonia Manduca ,&nbsp;Roberta Lattanzi","doi":"10.1016/j.cellsig.2025.111761","DOIUrl":"10.1016/j.cellsig.2025.111761","url":null,"abstract":"<div><div>Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in nociception and inflammation-induced hyperalgesia. Prokineticin receptors (PKR1 and PKR2) are G protein-coupled receptors (GPCRs) that are expressed both centrally and peripherally and induce various signalling pathways through the binding of their endogenous ligands, the prokineticins. The activation of PKRs is modulated by interaction with accessory proteins such as snapin and β-arrestin-2. The prokineticin system is involved in the mechanisms of pain perception by triggering a strong hyperalgesia that lowers the thresholds for thermal and mechanical stimuli. PKR1 and PKR2 are both expressed in dorsal root ganglia (DRG) neurons where they colocalise with TRPV1.</div><div>In this work, we have identified the regions that mediate the physical interaction between TRPV1 and PKR2. We demonstrated that in the presence of the accessory protein snapin, the strength of binding between TRPV1 and PKR2 is increased. TRPV1 proves to be a physiological regulator of PKR2, modulating its activation, localisation and β-arrestin binding as well as PK2-induced mechanical allodynia. The results obtained show for the first time that TRPV1 regulates PKR2 signalling, suggesting a bidirectional interaction between the two systems.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111761"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726101","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":"Methylophiopogonanone A alleviates diabetic cardiomyopathy via inhibiting JNK1 signaling","authors":"Jing Yin ,&nbsp;Zhicheng Song ,&nbsp;Lijun Zhang ,&nbsp;Jialin Cong","doi":"10.1016/j.cellsig.2025.111762","DOIUrl":"10.1016/j.cellsig.2025.111762","url":null,"abstract":"<div><h3>Objective</h3><div>Diabetic cardiomyopathy (DCM) is a common complication of type 2 diabetes mellitus (T2DM). The effects of methylophiopogonanone A (MO-A), a natural homoisoflavonoid with anti-inflammatory effects, on DCM and its underlying mechanisms were investigated in this study.</div></div><div><h3>Methods</h3><div>The T2DM mouse model was induced by intraperitoneal injection of 30 mg/kg streptozotocin for 7 consecutive days and fed with a high-fat diet for 12 weeks. T2DM mice received MO-A (2.5, 5, or 10 mg/kg) treatment for two weeks. Cardiac function, hypertrophy, fibrosis, and inflammation were evaluated. The binding energy between MO-A and JNK1 was analyzed using molecular docking. The underlying mechanism was further investigated in high glucose (HG)-induced H9C2 cells. The cytotoxic effects, cardiomyocyte hypertrophy, fibrosis, inflammation, and relevant signaling proteins were assessed.</div></div><div><h3>Results</h3><div>MO-A treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, MO-A treatment significantly decreased COL<img>I, TGF-β1, MYH7, and ANP expression levels in DCM mice. Furthermore, TNF-α, IL-6, and IL-1β expression levels were notably downregulated after treatment with MO-A in DCM mice. Similar results were also observed in vitro. Mechanistically, MO-A targets JNK1 and downregulates its phosphorylation levels in DCM mice. The protective properties of MO-A were reversed by JNK1 overexpression in HG-induced H9C2 cells.</div></div><div><h3>Conclusion</h3><div>Our results revealed that MO-A could alleviate cardiac function, hypertrophy, fibrosis, and inflammation in DCM via inhibiting JNK1 signaling.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111762"},"PeriodicalIF":4.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715629","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":"Periprosthetic osteolysis: Mechanisms and potential treatment strategies","authors":"Fang Yao ,&nbsp;Yue Bao ,&nbsp;Qian Meng ,&nbsp;Yanrong Chen ,&nbsp;Luxi Zhao ,&nbsp;Pingmei Wang ,&nbsp;Bin Zhou","doi":"10.1016/j.cellsig.2025.111758","DOIUrl":"10.1016/j.cellsig.2025.111758","url":null,"abstract":"<div><div>Periprosthetic osteolysis is a common bone-related disorder that often occurs after total hip arthroplasty. The implants can cause damage to bone and bone-related cells due to mechanical stress and micromotions, resulting in the generation of a large number of wear particles. These wear particles trigger inflammation and oxidative stress in the surrounding tissues, disrupting the delicate balance maintained by osteoblasts and osteoclasts, ultimately leading to bone loss around the implant. Clinical investigations have demonstrated that Epimedium prenylflavonoids, miR-19a-3p, stem cell-derived exosomes, and certain non-PPO category pharmaceuticals have regulatory effects on bone homeostasis through distinct molecular pathways. Notably, this phenomenon reflects inherent biological rationality rather than stochastic occurrence. Extensive research has revealed that multiple natural compounds, non-coding RNAs, exosomes, and non-PPO therapeutics not only exert modulatory influences on critical pathophysiological processes including inflammatory cascades, oxidative stress responses, and tissue regeneration mechanisms, but also effectively regulate bone-related cellular functions to inhibit PPO progression. Therefore, this review comprehensively and systematically summarizes the main pathogenic mechanisms of periprosthetic osteolysis. Furthermore, it delves deeper into the research progress on the applications of currently reported natural products, ncRNAs, exosomes, and non-PPO medications in the treatment of periprosthetic osteolysis. Based on this, we hope that this paper can provide new perspectives and references for the future development of drugs targeting periprosthetic osteolysis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111758"},"PeriodicalIF":4.4,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708884","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":"Function of intramitochondrial melatonin and its association with Warburg metabolism","authors":"Russel J. Reiter ,&nbsp;Ramaswamy Sharma ,&nbsp;Yidong Bai ,&nbsp;Luiz Gustavo de Almeida Chuffa ,&nbsp;Doris Loh ,&nbsp;Lihong Fan ,&nbsp;Daniel P. Cardinali","doi":"10.1016/j.cellsig.2025.111754","DOIUrl":"10.1016/j.cellsig.2025.111754","url":null,"abstract":"<div><div>Warburg metabolism (aerobic glycolysis) is accompanied by high mitochondrial reactive oxygen species (ROS) generation from the electron transport chain; this is a “Hallmark of Cancer”. The elevated ROS sustain the growth and proliferation of the cancer cells. Melatonin is a potent and functionally diverse free radical scavenger and antioxidant that is synthesized in the mitochondria of non-pathological cells and normally aids in keeping mitochondrial ROS levels low and in maintaining redox homeostasis. Because the glucose metabolite, pyruvate, does not enter mitochondria of Warburg metabolizing cells due to the inhibition of pyruvate dehydrogenase complex (PDH), acetyl coenzyme A production is diminished. Acetyl coenzyme A is a necessary co-substrate with serotonin for melatonin synthesis; thus, intramitochondrial melatonin levels become reduced in cancer cells. The hypothesis is that the depressed melatonin levels initiate aerobic glycolysis and allow the exaggerated ROS concentrations to go uncontested; the authors speculate that the elevated mtROS upregulates hypoxia inducible factor 1α (HIF-1α)/pyruvate dehydrogenase kinase (PDK) axis which inhibits PDH, thereby supporting cancer cell proliferation and stimulating cancer biomass. Exposing Warburg metabolizing cancer cells to melatonin elevates intramitochondrial melatonin, thereby reducing mtROS and concurrently interrupting aerobic glycolysis and inhibiting tumor cell proliferation. Mechanistically, higher mitochondrial melatonin levels by supplementation directly upregulates the sirtuin 3 (SIRT3)/FOXO/PDH axis, allowing pyruvate entry into mitochondria and enhancing intrinsic mitochondrial melatonin production as in non-pathological cells. Additionally, melatonin inhibits HIF1α, thereby decreasing PDK activity and disinhibiting PDH, so pyruvate enters mitochondria and is metabolized to acetyl coenzyme A, resulting in reversal of Warburg metabolism.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111754"},"PeriodicalIF":4.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683291","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":"SIRT6 mitigates acute kidney injury by enhancing lipid metabolism and reducing tubular epithelial cell apoptosis via suppression of the ACMSD signaling pathway","authors":"Dan Wang ,&nbsp;Yugang Zhou ,&nbsp;Na Yang ,&nbsp;Jingjing Liu ,&nbsp;Li Lu ,&nbsp;Zhao Gao","doi":"10.1016/j.cellsig.2025.111757","DOIUrl":"10.1016/j.cellsig.2025.111757","url":null,"abstract":"<div><div>Acute kidney injury (AKI) remains a critical condition with substantial morbidity and mortality in hospitalized patients. Emerging research has underscored the protective role of SIRT6 in kidney diseases through diverse signaling pathways. Our current report aimed to elucidate the mechanisms by which SIRT6 mitigated the progression of AKI. Immunohistochemical and Oil Red O staining techniques were employed to assess the expression of SIRT6 and lipid metabolism in both AKI patients and AKI mice treated with UBCS039, a specific SIRT6 activator (30 mg/kg, i.p.). Kidney tissues from AKI mice were analyzed using LC-MS/MS to uncover SIRT6-related signaling pathways involved in AKI. Additionally, human proximal renal tubule cells (HK−2) were exposed to UBCS039 or transfected pcDNA3.1-SIRT6 overexpression plasmid to investigate the underlying signaling mechanisms of SIRT6 on lipid metabolism using Western blotting analysis and Oil Red O staining. Gene expression levels of ACMSD was detected by qRT-PCR and Western blotting in HK-2 cells. Dual-luciferase reporter assay was used to verify the effect of SIRT6 on regulating ACMSD transcription. Our findings revealed a significant reduction in SIRT6 expression in both AKI patients and AKI mice. Treatment with UBCS039, however, significantly decreased lipid accumulation and apoptosis in AKI mice. Proteomic analysis and Dual-luciferase reporter assay identified ACMSD as a downstream target of SIRT6. In vitro studies further demonstrated that SIRT6 enhanced lipid metabolism and mitigated apoptosis through the inhibition of ACMSD expression. This study demonstrated that SIRT6 promoted lipid metabolism by inhibiting the ACMSD pathway, thereby reducing apoptosis in AKI. These findings suggested that targeting ACMSD could offer a novel therapeutic strategy for SIRT6-mediated intervention in AKI.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111757"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683188","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":"Apatinib combined with paclitaxel suppresses synergistically TNBC progression through enhancing ferroptosis susceptibility regulated SLC7A11/GPX4/ACSL4 axis","authors":"Xiaoxia Ma ,&nbsp;Di Cao ,&nbsp;Yan Zhang ,&nbsp;Xiaoyun Ding ,&nbsp;Zhiqiang Hu ,&nbsp;Jing Wang","doi":"10.1016/j.cellsig.2025.111760","DOIUrl":"10.1016/j.cellsig.2025.111760","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is highly heterogeneous, often leading to resistance to chemotherapy agents like paclitaxel (PTX) and resulting in suboptimal outcomes. The anti-angiogenic agent apatinib not only enhances chemotherapy sensitivity but also involves in regulating ferroptosis. However, the potential of combining apatinib with PTX to improve treatment efficacy in refractory TNBC by increasing tumor cell susceptibility to ferroptosis remains elusive. This study aims to elucidate whether inducing ferroptosis participates in the beneficial effects of apatinib combined with PTX to synergistically suppress TNBC. Herein, we demonstrated that the coadministration of apatinib and PTX exerted significant inhibitory effects on both primary tumor progression and distant metastases to pulmonary and hepatic tissues in TNBC-bearing murine models. Transcriptomic and proteomic analyses indicated that ferroptosis induction is a key mechanism by which the drug combination suppresses TNBC, as evidenced by a marked downregulation of SLC7A11, GPX4, NRF2, and FTH1, and a significant upregulation of ACSL4. In vitro, the combination of 5 μM apatinib and 8 nM PTX synergistically inhibited tumor cell proliferation, migration, and invasion. Notably, the combination therapy markedly augmented ferroptosis in tumor cells through the regulation of the SLC7A11/GPX4/ACSL4 axis, leading to increased intracellular iron accumulation and lipid peroxide generation, concomitant with a reduction in GSH levels. The effect of apatinib combined with PTX on enhancing ferroptosis susceptibility could be exploited as a combination treatment regimen for future TNBC therapy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111760"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683190","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":"MCC in the spotlight: Its dual role in signal regulation and oncogenesis","authors":"Soohyeon Lee ,&nbsp;Beomwoo Lee ,&nbsp;So Hee Kwon ,&nbsp;Jongsun Park ,&nbsp;Seon-Hwan Kim","doi":"10.1016/j.cellsig.2025.111756","DOIUrl":"10.1016/j.cellsig.2025.111756","url":null,"abstract":"<div><div>The mutated in colorectal cancer (<em>MCC</em>) gene is closely associated with the onset and progression of colorectal cancer. <em>MCC</em> plays a critical role in regulating the cell cycle and various signaling pathways and is recognized to inhibit cancer cell proliferation via the β-catenin signaling pathway. β-catenin is a key component of the WNT signaling pathway that influences cell growth, differentiation, survival, and migration, thereby positioning <em>MCC</em> as an important tumor suppressor. Notably, <em>MCC</em> has also been implicated in other cancer types, including lung, liver, and brain cancers. However, the precise mechanisms by which <em>MCC</em> functions in these malignancies remain inadequately understood. Comprehensive investigations into the interactions among <em>MCC</em>, various signaling pathways, and metabolic processes are essential for uncovering the molecular mechanisms of cancer and the pathological features characteristic of different cancer stages. This review presents the structural characteristics of <em>MCC</em> and its cell growth regulation mechanisms and functional roles within tissues, with the aims of enhancing our understanding of the role of <em>MCC</em> in cancer biology and highlighting potential therapeutic strategies targeting this gene.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111756"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673333","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":"Fibroblast-derived versican exacerbates periodontitis progression by regulating macrophage migration and inflammatory cytokine secretion","authors":"Yuting Yang ,&nbsp;Li Li ,&nbsp;Fang Dai ,&nbsp;Libin Deng ,&nbsp;Kaiqiang Yang ,&nbsp;Chenjiang He ,&nbsp;Yeke Chen ,&nbsp;Xinbo Yang ,&nbsp;Li Song","doi":"10.1016/j.cellsig.2025.111755","DOIUrl":"10.1016/j.cellsig.2025.111755","url":null,"abstract":"<div><h3>Objective</h3><div>Versican (VCAN), a prominent extracellular matrix component upregulated in inflammatory diseases, demonstrates context-specific regulatory mechanisms. Periodontitis, a chronic inflammatory disease leading to periodontal tissue destruction and tooth loss, the pathological role of it remains poorly defined. Our study aims to examine VCAN-mediated mechanisms in periodontitis.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive analysis of bulk RNA sequencing and single-cell RNA sequencing data to examine VCAN expression level and source in periodontitis. Functional and correlation analyses were used to explore its biological functions. We then validated VCAN expression using quantitative real-time polymerase chain reaction, immunohistochemical staining, and immunofluorescence staining in animal models and investigated its biological functions in inflammation through in vitro experiments.</div></div><div><h3>Results</h3><div>Our findings reveal that VCAN is mainly generated by fibroblast in periodontitis, and its expression significantly upregulated at both mRNA and protein levels. Using VCAN-overexpressing L929 cells, we demonstrated enhanced proliferative capacity and inflammatory potential. Co-culture experiments with RAW264.7 cells showed promoted migration, adhesion, M1 polarization, and mitogen-activated protein kinase (MAPK) pathway activation.</div></div><div><h3>Conclusion</h3><div>VCAN enhances fibroblast proliferation and migration, and upregulates inflammatory cytokines expression. Furthermore, fibroblast-derived VCAN not only induces macrophage chemotaxis, migration, adhesion, and polarization toward the proinflammatory M1 phenotype, but also activates MAPK signaling of macrophage, which may amplify inflammatory cascades to exacerbate periodontal tissue destruction. Targeted regulation of VCAN expression may become a promising precision treatment strategy for periodontitis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111755"},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669119","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 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}