Cellular signalling最新文献

{"title":"Free fatty acids derived from lipophagy enhanced resistance to anoikis by activating Src in high-invasive clear cell renal cell carcinoma cells","authors":"Mengmeng Wu ,&nbsp;Guijuan Chen ,&nbsp;Xin Li ,&nbsp;Wenliang Ma ,&nbsp;Yi Chen ,&nbsp;Yi Gong ,&nbsp;Hao Zheng ,&nbsp;Gongming Gu ,&nbsp;Yibing Ding ,&nbsp;Ping Dong ,&nbsp;Weidong Ding ,&nbsp;Luqing Zhang ,&nbsp;Weidong Gan ,&nbsp;Dongmei Li","doi":"10.1016/j.cellsig.2025.111622","DOIUrl":"10.1016/j.cellsig.2025.111622","url":null,"abstract":"<div><div>Autophagy-mediated anoikis resistance plays a critical role in the initiation of tumor metastasis. Therefore, we investigated the role and mechanism of anoikis resistance mediated by free fatty acids (FFAs) derived from lipophagy in highly invasive clear cell renal cell carcinoma (ccRCC). Here, we found that the highly invasive ccRCC cell line Himi exhibited enhanced resistance to anoikis and elevated lipophagy levels. The increased lipophagy observed in Himi ccRCC cells contributed to their resistance to anoikis. The nonreceptor tyrosine kinase Src was significantly upregulated in Himi cells cultured under suspension conditions and in patients with poor prognoses. The underlying mechanism revealed that the FFAs released from lipophagy activated the phosphorylated Tyr419 site of Src, thereby promoting ccRCC invasion, facilitating epithelial–mesenchymal transition (EMT), enhancing angiogenesis, and conferring resistance to anoikis. Therefore, the present study revealed that FFAs generated from the degradation of lipid droplets <em>via</em> lipophagy enhanced resistance to anoikis by activating the phosphorylated Tyr419 site of Src in highly invasive ccRCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111622"},"PeriodicalIF":4.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058323","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":"HDAC2 promotes colorectal tumorigenesis by triggering dysregulation of lipid metabolism through YAP1","authors":"Zhanghan Chen ,&nbsp;Weifeng Hong ,&nbsp;Bing Li ,&nbsp;Dongli He ,&nbsp;Zhong Ren ,&nbsp;Mingyan Cai ,&nbsp;Yirong Cheng ,&nbsp;Jingyi Liu ,&nbsp;Enpan Xu ,&nbsp;Yanyun Du ,&nbsp;Yuelun Dong ,&nbsp;Shilun Cai ,&nbsp;Qiang Shi ,&nbsp;Zhipeng Qi ,&nbsp;Yunshi Zhong","doi":"10.1016/j.cellsig.2025.111627","DOIUrl":"10.1016/j.cellsig.2025.111627","url":null,"abstract":"<div><div>Dysfunction of lipid metabolism is important for the development and progression of colorectal cancer, but the underlying mechanisms remain unclear. Here, HDAC2 was identified as highly expressed in both adenoma and colorectal cancer. We aimed to explore the roles and mechanisms of HDAC2 in lipid metabolism in colorectal cancer. HDAC2 expression in adenoma and colorectal cancer tissues was measured using tissue arrays. The function of HDAC2/YAP1 was identified using in vitro and in vivo experiments. Coimmunoprecipitation experiments, DNA pull-down assays, luciferase analyses, and ChIP-qPCR (Chromatin Immunoprecipitation-quantitative real-time polymerase chain reaction) assays were used to identify the potential mechanisms of HDAC2. We found that HDAC2 can disrupt lipid metabolism in colorectal cancer by mediating the deacetylation of YAP1. Mechanistically, HDAC2 can bind to YAP1 and mediate deacetylation of the K280 site of YAP1. Furthermore, the deacetylation of YAP1 reduces the efficiency of its binding to the ZMYND11 promoter region, exacerbating lipid metabolism disorders, which in turn reduce lipid accumulation and increase lipid catabolism in colorectal cancer cells. Our study identified a novel regulatory mechanism of lipid metabolism in colorectal cancer in which HDAC2 increases lipid catabolism by regulating the deacetylation of the K280 site of YAP1, revealing that HDAC2 promotes tumor progression through the regulation of lipid metabolism.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"128 ","pages":"Article 111627"},"PeriodicalIF":4.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058325","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":"Zn2+ protects H9C2 cardiomyocytes by alleviating MAMs-associated apoptosis and calcium signaling dysregulation","authors":"Jiabao Guo ,&nbsp;Tingting Ma ,&nbsp;Bingyu Wang ,&nbsp;Bohan Xing ,&nbsp;Luyao Huang ,&nbsp;Xiaoyi Li ,&nbsp;Huan Zheng ,&nbsp;Yonggui He ,&nbsp;Jinkun Xi","doi":"10.1016/j.cellsig.2025.111629","DOIUrl":"10.1016/j.cellsig.2025.111629","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aims to investigate whether zinc ion (Zn²⁺) alleviates myocardial ischemia-reperfusion injury (MIRI) through the MAM-associated signaling pathway and to explore its impact on ERS and calcium overload.</div></div><div><h3>Methods</h3><div>H9C2 cells were cultured in a DMEM supplemented with 10 % fetal bovine serum and 1 % antibiotic solution. A MIRI model was established through simulated ischemia and reoxygenation with Zn²⁺ treatment in a complete medium. Cells were then treated with the MCU inhibitor ruthenium red (RR), the MCU activator spermine (SP), and siRNAs targeting Bap31, MCU, VDAC1, and FUNDC1. Cell viability was assessed using MTT and CCK-8 assays. Lactate dehydrogenase (LDH) levels were measured with a commercial kit. Western blot was performed to detect protein expression levels. Cell apoptosis, intracellular zinc, calcium levels, mitochondrial membrane potential, and protein fluorescence changes were observed using laser scanning confocal microscopy.</div></div><div><h3>Results</h3><div>Compared to the control group, cell viability was significantly reduced in the I/R group, accompanied by increased expression of apoptosis and calcium overload-related proteins increased cell injury, apoptosis, calcium overload, and a decrease in mitochondrial membrane potential. Zn²⁺ treatment reversed the detrimental effects of I/R in the I/R + Zn²⁺ group. When Bap31, VDAC1, FUNDC1, or MCU were silenced using siRNA, the protective effect of Zn²⁺ was further enhanced (<em>P</em> &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>Ischemia-reperfusion (I/R) leads to cardiomyocyte injury and apoptosis. Zn²⁺ downregulates the expression of key apoptotic proteins through the Bap31/Fis1 pathway and regulates MCU activity through the IP3R1-GRP75-VDAC1 and IP3R2/FUNDC1 pathways to alleviate calcium overload and ultimately protect cardiomyocytes after I/R.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111629"},"PeriodicalIF":4.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051830","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":"ANXA2 promotes chondrocyte differentiation and fracture healing by regulating the phosphorylation of STAT3 and PI3K/AKT signaling pathways","authors":"Xinru Wang,&nbsp;Wei Dong,&nbsp;Xinyi Wang,&nbsp;Jiawei Wang","doi":"10.1016/j.cellsig.2025.111617","DOIUrl":"10.1016/j.cellsig.2025.111617","url":null,"abstract":"<div><div>Fractures are common and serious skeletal injuries, and accelerating their healing while alleviating patient suffering remains a clinical challenge. Annexin A2 (ANXA2) is a widely distributed, calcium-dependent, phospholipid-binding protein involved in bone remodeling. However, its role in chondrocyte differentiation and endochondral ossification remains unclear. In this study, we found that ANXA2 is expressed in chondrocytes during growth plate development and fracture healing, as well as during chondrocyte differentiation and maturation <em>in vitro</em>, with its highest expression occurring in the most active differentiation phase. Moreover, ANXA2 knockdown inhibited chondrocyte differentiation, while its overexpression significantly promoted it. We also demonstrated that ANXA2 regulates the chondrogenic and hypertrophic differentiation by mediating the phosphorylation and nuclear translocation of STAT3, as well as activating the PI3K/AKT pathway. Finally, recombinant ANXA2 protein was injected into the tibial fracture sites of mice, verifying its role in promoting endochondral ossification during fracture healing. In conclusion, our study shows that ANXA2 promotes chondrocyte differentiation, partially through the STAT3 and PI3K/AKT pathways. These findings provide insights that could aid in developing new therapies to enhance fracture healing.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111617"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037358","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":"Dichloroacetate: A metabolic game-changer in alleviating macrophage inflammation and enhancing recovery after myocardial infarction","authors":"Fuyou Lv ,&nbsp;Ning Qi ,&nbsp;Chang Liu ,&nbsp;Lili Wang ,&nbsp;Tianning Dai ,&nbsp;Hai Tian","doi":"10.1016/j.cellsig.2025.111618","DOIUrl":"10.1016/j.cellsig.2025.111618","url":null,"abstract":"<div><h3>Background</h3><div>Dichloroacetate (DCA) has shown potential in modulating cellular metabolism and inflammation, particularly in cardiac conditions. This study investigates DCA's protective effects in a mouse model of myocardial infarction (MI), focusing on its ability to enhance cardiac function, reduce inflammation, and shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype.</div></div><div><h3>Methods</h3><div>An acute MI model was created using left anterior descending coronary artery ligation. Mice were assigned to four groups: normal control, MI control, MI + 50 mM DCA, and MI + 100 mM DCA. Cardiac fibrosis and injury were assessed through H&amp;E staining. Cardiac function was evaluated via echocardiography, and serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Inflammation and apoptosis were analyzed through immunohistochemistry, ELISA, western blotting, and flow cytometry in heart tissue and RAW264.7 cells. Additionally, macrophage polarization and relevant signaling pathways were examined.</div></div><div><h3>Results</h3><div>DCA significantly improved cardiac function in MI mice, evidenced by reduced myocardial injury and lower CK-MB and LDH levels. It also decreased inflammatory cytokines (TNF-α, IL-6 and IL-1β) and facilitated macrophage polarization from M1 to M2. Western blotting revealed that DCA inhibited iNOS and COX2 while enhancing Arg1 expression, alongside improved mitochondrial function and reduced apoptosis. Additionally, by injecting AAV-PDHK4 (pyruvate dehydrogenase kinase) into MI mice, we found that DCA effectively inhibited the progression of MI through the suppression of PDHK4.</div></div><div><h3>Conclusion</h3><div>DCA protects against myocardial infarction by enhancing cardiac function, reducing inflammation, and promoting macrophage polarization, likely through inhibition of PDHK4 and NF-κB pathways, positioning it as a potential therapeutic strategy for cardiac repair post-MI.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111618"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037360","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":"METTL14-mediated depression of NEIL1 aggravates oxidative damage and mitochondrial dysfunction of lens epithelial cells through regulating KEAP1/NRF2 pathways","authors":"Lihua Kang ,&nbsp;Sijie Bao ,&nbsp;Pengfei Li ,&nbsp;Guowei Zhang ,&nbsp;Xi Zhu,&nbsp;Min Ji,&nbsp;Huaijin Guan","doi":"10.1016/j.cellsig.2025.111623","DOIUrl":"10.1016/j.cellsig.2025.111623","url":null,"abstract":"<div><div>Abnormal base excision repair (BER) pathway and N6-methyladenosine (m6A) of RNA have been proved to be significantly related to age-related cataract (ARC) pathogenesis. However, the relationship between the Nei Endonuclease VIII-Like1 (NEIL1) gene (a representative DNA glycosylase of BER pathway) and its m6A modification remains unclear. Here, we showed that the expression of NEIL1 was decreased in the ARC anterior lens capsules and H₂O₂-stimulated SRA01/04 cells. Our findings demonstrated that ectopic expression of NEIL1 alleviated DNA oxidative damage, apoptosis and mitochondrial dysfunction through disturbing KEAP1/NRF2 interaction. Furthermore, silencing NEIL1 aggravated H₂O₂-induced lens opacity, whereas ML334 could mitigate lens cloudy ex vitro in rat lenses. Besides, intravitreal injection of AAV2-NEIL1 alleviated lens opacity in Emory mice in vivo. Mechanistically, the N(6)-Methyladenosine (m6A) methyltransferase-like 14 (METTL14) was identified as a factor in promoting m6A modification of NEIL1, which resulted in the recruitment of YTHDF2 to recognize and impair NEIL1 RNA stability. Collectively, these findings highlight the critical role of the m6A modification in NEIL1 on regulating oxidative stress and mitochondrial homeostasis through KEAP1/NRF2 pathways, providing a new way to explore the pathogenesis of ARC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111623"},"PeriodicalIF":4.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037361","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":"D-Ala2-GIP (1−30) promotes angiogenesis by facilitating endothelial cell migration via the Epac/Rap1/Cdc42 signaling pathway","authors":"Tuchen Guan ,&nbsp;Wenxue Zhang ,&nbsp;Mingxuan Li ,&nbsp;Qing Wang ,&nbsp;Longyu Guo ,&nbsp;Beibei Guo ,&nbsp;Xiaoqian Luo ,&nbsp;Zhen Li ,&nbsp;Muxing Lu ,&nbsp;Zhangji Dong ,&nbsp;Man Xu ,&nbsp;Mei Liu ,&nbsp;Yan Liu ,&nbsp;Jian Feng","doi":"10.1016/j.cellsig.2025.111615","DOIUrl":"10.1016/j.cellsig.2025.111615","url":null,"abstract":"<div><div>Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111615"},"PeriodicalIF":4.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037359","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":"KGF impedes TRIM21-enhanced stabilization of keratin 10 mediating differentiation in hypopharyngeal cancer","authors":"Fangyu Chai ,&nbsp;Guangyi Wang ,&nbsp;Yibang Shen ,&nbsp;Yanfang Niu ,&nbsp;Yichuan Huang ,&nbsp;Tao Fu ,&nbsp;Tao Yang ,&nbsp;Yan Jiang ,&nbsp;Jisheng Zhang","doi":"10.1016/j.cellsig.2025.111614","DOIUrl":"10.1016/j.cellsig.2025.111614","url":null,"abstract":"<div><div>KGF, also known as FGF7, is a member of the fibroblast growth factor (FGF) family that binds with high affinity to the FGF receptor 2b (FGFR2b) and regulates various cellular processes, including cell proliferation and differentiation in a variety of tumors. However, its potential role in hypopharyngeal cancer (HPC) remains largely unknown. In our study, we observed increased expression of FGFR2b in HPC. KGF treatment inhibited the expression of the differentiation marker keratin 10 (K10) protein at the post-transcriptional level in FaDu cells. Furthermore, treatment with the proteasome inhibitor MG132 was found to attenuate KGF-induced K10 reduction, suggesting the involvement of the ubiquitin-proteasome system. Using mass spectrometry and immunoprecipitation analysis, we identified the E3 ubiquitin ligase TRIM21 as a K10-interacting protein. Unexpectedly, instead of causing degradation, TRIM21 enhanced K10 protein stability through K6-linked ubiquitination of K10 at lysine 163 (K163) in the context of KGF exposure. Meanwhile, KGF treatment decreased TRIM21 protein levels, which were regulated by the p38 MAPK pathway, leading to K48-linked ubiquitination-mediated degradation of TRIM21. Notably, TRIM21 knockdown significantly promoted proliferation, inhibited differentiation and migration of FaDu cells, whereas TRIM21 overexpression had opposite effects in vitro and suppressed xenograft tumor growth in vivo. Our study demonstrates that TRIM21 may act as a tumor suppressor in HPC. However, TRIM21 overexpression decreased the sensitivity of FaDu cells to 5-fluorouracil, whereas TRIM21 knockdown or KGF administration significantly increased 5-fluorouracil sensitivity. Taken together, these findings highlight the intricate balance between protein stabilization and degradation orchestrated by KGF. This ubiquitination-mediated non-degradation mechanism of TRIM21 may provide novel therapeutic strategies for HPC and other cancers.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111614"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028061","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":"SRF and CBP jointly regulate integrin β6 overexpression in head and neck squamous cell carcinomas","authors":"Mingyan Xu ,&nbsp;Gongwei Luo ,&nbsp;Yixin Xiao ,&nbsp;Feixiang Zhu ,&nbsp;Hongfa Yao ,&nbsp;Haohao Zhu ,&nbsp;Fan Liu ,&nbsp;Songlin Shi ,&nbsp;Xiaoling Deng","doi":"10.1016/j.cellsig.2025.111621","DOIUrl":"10.1016/j.cellsig.2025.111621","url":null,"abstract":"<div><div>Overexpression of integrin β6 (ITGB6) is crucially linked to the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms driving <em>ITGB6</em> upregulation in HNSCC are not well understood. Our study comprehensively analyzed the transcriptional regulation and epigenetic modification mechanisms affecting <em>ITGB6</em> transcription. We retrospectively evaluated ITGB6 expression using immunohistochemistry on a tissue microarray. Elevated ITGB6 expression in HNSCC specimens correlates with poor clinical prognosis. Using a luciferase reporter assay, site-directed mutagenesis, RNA interference, chromatin immunoprecipitation assay, and a 4-nitroquinoline 1-oxide (4NQO)-induced murine HNSCC model, we have demonstrated that the transcription factor Serum Response Factor (SRF) upregulates <em>ITGB6</em> transcription. Our results further demonstrated that the histone acetyltransferase (HAT) CBP mediates the hyperacetylation of histones H3 and H4, facilitating their recruitment to the <em>ITGB6</em> promoter. This recruitment strengthens SRF binding to the <em>ITGB6</em> promoter. These findings suggest that SRF and CBP-mediated histone hyperacetylation are crucial for ITGB6 overexpression in HNSCC. Epigenetic mechanisms play a critical role in the active transcriptional expression of <em>ITGB6</em> in HNSCC cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111621"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028062","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":"HMGB1 secretion by resveratrol in NSCLC: A pathway to ferroptosis-mediated platelet activation suppression","authors":"Yifan Zhang ,&nbsp;Shihao Bao ,&nbsp;Jingtong Zeng ,&nbsp;Jingyu Liu ,&nbsp;Xianjie Li ,&nbsp;Bo Zhang ,&nbsp;Hanqing Wang ,&nbsp;Yuan Cheng ,&nbsp;Hao Zhang ,&nbsp;Wei Xia ,&nbsp;Lingling Zu ,&nbsp;Xiaohong Xu ,&nbsp;Song Xu ,&nbsp;Zuoqing Song","doi":"10.1016/j.cellsig.2025.111607","DOIUrl":"10.1016/j.cellsig.2025.111607","url":null,"abstract":"<div><h3>Background</h3><div>Cancer-associated venous thromboembolism (CAT) is a frequent and serious complication in cancer patients. Resveratrol, a natural compound with reported anti-tumor effects, is not fully understood in its role regarding CAT in lung cancer. This study aims to explore resveratrol's potential to diminish platelet activation induced by lung adenocarcinoma cells and uncover the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Clinical data on coagulation function in non-small cell lung cancer (NSCLC) patients were gathered. A549 human lung cancer cells and Lewis mouse lung cancer cells were employed to assess tumor-induced platelet activation and the impact of resveratrol on this process. Western blotting analyzed protein expression, electron microscopy examined extracellular vesicle (EV) morphology, flow cytometry measured platelet activation, reactive oxygen species (ROS), and exocrine protein expression, while ELISA quantified secretory proteins. Tumor control and platelet function were studied in tumor-bearing mice.</div></div><div><h3>Results</h3><div>We identified that hematological profiles of NSCLC patients frequently manifest a hypercoagulable state relative to healthy controls and lung cancer cells could instigate platelet activation, yet resveratrol could attenuate this phenomenon induced by lung cancer. Resveratrol stimulates lung cancer cells to release HMGB1-enriched EVs, promoting platelet ferroptosis and inhibiting platelet activation through increased ROS, lipid peroxidation, and disrupted cystine transporters. In vivo studies confirm that resveratrol inhibits lung cancer cell growth and suppresses tumor-induced platelet activation in mice.</div></div><div><h3>Conclusion</h3><div>Our studies revealed that resveratrol alleviated lung cancer-induced ferroptosis associated platelet activation. This suggests a potential pharmacological approach for preventing and treating both lung cancer and CAT.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111607"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022380","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}