Pub Date : 2026-06-01Epub Date: 2026-01-31DOI: 10.1016/j.cellsig.2026.112378
Haipeng Wang , Ying Feng , Wei Jiang , Han Wang , Ruolin Zhang , Guangqiang Li , Chao Duan , Yuneng Zhou , Wendai Bao , Ke Shui , Min Zhang , Zhibing Ai , Xin Yang , Peiyang Zhou , Zhiqiang Dong
Riluzole, an FDA-approved neuroprotective agent, was investigated for its therapeutic potential in ischemic stroke. Transcriptomic profiling of human brain microvascular endothelial cells (hBMECs) subjected to oxygen-glucose deprivation/reperfusion (OGD/R) identified a pivotal role for the cystine/glutamate antiporter SLC7A11. We found that riluzole activates SLC7A11, thereby triggering a dual protective mechanism: it strengthens cellular antioxidant capacity by upregulating GPX4 while simultaneously enhancing proangiogenic signaling through the HIF-1α/VEGFA pathway. Consequently, riluzole attenuated OGD/R-induced endothelial injury and, in a mouse stroke model, reduced blood–brain barrier disruption and improved neurological outcomes. Our study reveals a previously unrecognized cerebrovascular protective mechanism of riluzole, establishing SLC7A11 as its key mediator. This SLC7A11-dependent dual-pathway action represents a substantive advance in understanding riluzole's therapeutic biology beyond its established roles in the central nervous system.
{"title":"Riluzole preserves brain endothelial integrity in ischemic stroke via SLC7A11-dependent GPX4 and HIF-1α/VEGFA signaling","authors":"Haipeng Wang , Ying Feng , Wei Jiang , Han Wang , Ruolin Zhang , Guangqiang Li , Chao Duan , Yuneng Zhou , Wendai Bao , Ke Shui , Min Zhang , Zhibing Ai , Xin Yang , Peiyang Zhou , Zhiqiang Dong","doi":"10.1016/j.cellsig.2026.112378","DOIUrl":"10.1016/j.cellsig.2026.112378","url":null,"abstract":"<div><div>Riluzole, an FDA-approved neuroprotective agent, was investigated for its therapeutic potential in ischemic stroke. Transcriptomic profiling of human brain microvascular endothelial cells (hBMECs) subjected to oxygen-glucose deprivation/reperfusion (OGD/R) identified a pivotal role for the cystine/glutamate antiporter SLC7A11. We found that riluzole activates SLC7A11, thereby triggering a dual protective mechanism: it strengthens cellular antioxidant capacity by upregulating GPX4 while simultaneously enhancing proangiogenic signaling through the HIF-1α/VEGFA pathway. Consequently, riluzole attenuated OGD/R-induced endothelial injury and, in a mouse stroke model, reduced blood–brain barrier disruption and improved neurological outcomes. Our study reveals a previously unrecognized cerebrovascular protective mechanism of riluzole, establishing SLC7A11 as its key mediator. This SLC7A11-dependent dual-pathway action represents a substantive advance in understanding riluzole's therapeutic biology beyond its established roles in the central nervous system.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112378"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104174","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}
Pub Date : 2026-06-01Epub Date: 2026-02-18DOI: 10.1016/j.cellsig.2026.112433
Jiabao Gao , Yanchun Pan , Quan Cheng , Songbo Wang , Haotian Chen , Xuezhi Long , Yueting Huang , Zhanpeng Liu , Ziyi Li , Di Gu , Shancheng Ren
Lymphatic metastasis is the most common route of dissemination in bladder cancer and is closely associated with poor clinical outcomes, posing a major challenge to effective treatment. Therefore, identifying the key initiators and regulators of lymphatic metastasis in bladder cancer may provide promising targets for its prevention and therapy. In this study, we report that USP43 is highly expressed in lymph node metastatic bladder cancer. USP43 promotes lymphangiogenesis and lymph node metastasis in both in vitro and in vivo models. Mechanistically, USP43 deubiquitinates and thereby stabilized ZBTB7A. As a transcription factor, ZBTB7A promotes lymphangiogenesis and facilitates lymph node metastasis by upregulating the transcription of VEGFA and activating AKT pathway. Collectively, our findings reveal that the USP43/ZBTB7A axis plays a crucial role in promoting lymphatic metastasis of bladder cancer, offering potential therapeutic and preventive strategies for lymph node metastatic bladder cancer.
{"title":"USP43 promotes lymphatic metastasis of bladder cancer by regulation of ZBTB7A","authors":"Jiabao Gao , Yanchun Pan , Quan Cheng , Songbo Wang , Haotian Chen , Xuezhi Long , Yueting Huang , Zhanpeng Liu , Ziyi Li , Di Gu , Shancheng Ren","doi":"10.1016/j.cellsig.2026.112433","DOIUrl":"10.1016/j.cellsig.2026.112433","url":null,"abstract":"<div><div>Lymphatic metastasis is the most common route of dissemination in bladder cancer and is closely associated with poor clinical outcomes, posing a major challenge to effective treatment. Therefore, identifying the key initiators and regulators of lymphatic metastasis in bladder cancer may provide promising targets for its prevention and therapy. In this study, we report that USP43 is highly expressed in lymph node metastatic bladder cancer. USP43 promotes lymphangiogenesis and lymph node metastasis in both in vitro and in vivo models. Mechanistically, USP43 deubiquitinates and thereby stabilized ZBTB7A. As a transcription factor, ZBTB7A promotes lymphangiogenesis and facilitates lymph node metastasis by upregulating the transcription of VEGFA and activating AKT pathway. Collectively, our findings reveal that the USP43/ZBTB7A axis plays a crucial role in promoting lymphatic metastasis of bladder cancer, offering potential therapeutic and preventive strategies for lymph node metastatic bladder cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112433"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257660","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}
Pub Date : 2026-06-01Epub Date: 2026-02-26DOI: 10.1016/j.cellsig.2026.112452
Ruitong Tang , Zhongqian Juan , Fangtao Xing , Zhengjun Yi , Yurong Fu
Lung cancer (LC), a leading cause of cancer-related mortality globally, relies on intricate crosstalk within the tumor microenvironment (TME) to drive immune evasion and therapeutic resistance. Exosomes serve as key mediators of intercellular communication within the TME. They regulate molecular signaling between tumor cells and their microenvironment in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Exosomes carry a variety of bioactive substances. These substances work together to impair the immune system, speed up the growth of tumors, encourage invasion and metastasis, and exacerbate therapeutic resistance. Tumor-derived exosomes (TEXs) facilitate immune evasion by impairing cytotoxic T lymphocytes (CTLs) function, promoting regulatory T cells (Tregs) differentiation, and polarizing macrophages toward the tumor-supportive M2 phenotype. Exosomes also make cells more resistant to chemotherapy, targeted treatment, and immunotherapy by changing the way cells send signals, changing the TME to help cells stay alive, and sending proteins that make cells more resistant. Due to their stability and detectability in bodily fluids, exosomes represent promising noninvasive biomarkers for LC diagnosis, prognosis, and treatment monitoring. Translational strategies targeting exosome biogenesis, release, or uptake, as well as modified exosomes for targeted drug delivery and immune modulation, hold potential to overcome treatment resistance and improve clinical outcomes. This review summarizes the core mechanisms of exosome-mediated immune evasion and therapeutic resistance in LC, and highlights their key translational implications for clinical application.
{"title":"Exosome-mediated crosstalk between immune cells and tumor microenvironment in lung cancer: Implications for immune evasion and therapeutic resistance","authors":"Ruitong Tang , Zhongqian Juan , Fangtao Xing , Zhengjun Yi , Yurong Fu","doi":"10.1016/j.cellsig.2026.112452","DOIUrl":"10.1016/j.cellsig.2026.112452","url":null,"abstract":"<div><div>Lung cancer (LC), a leading cause of cancer-related mortality globally, relies on intricate crosstalk within the tumor microenvironment (TME) to drive immune evasion and therapeutic resistance. Exosomes serve as key mediators of intercellular communication within the TME. They regulate molecular signaling between tumor cells and their microenvironment in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Exosomes carry a variety of bioactive substances. These substances work together to impair the immune system, speed up the growth of tumors, encourage invasion and metastasis, and exacerbate therapeutic resistance. Tumor-derived exosomes (TEXs) facilitate immune evasion by impairing cytotoxic T lymphocytes (CTLs) function, promoting regulatory T cells (Tregs) differentiation, and polarizing macrophages toward the tumor-supportive M2 phenotype. Exosomes also make cells more resistant to chemotherapy, targeted treatment, and immunotherapy by changing the way cells send signals, changing the TME to help cells stay alive, and sending proteins that make cells more resistant. Due to their stability and detectability in bodily fluids, exosomes represent promising noninvasive biomarkers for LC diagnosis, prognosis, and treatment monitoring. Translational strategies targeting exosome biogenesis, release, or uptake, as well as modified exosomes for targeted drug delivery and immune modulation, hold potential to overcome treatment resistance and improve clinical outcomes. This review summarizes the core mechanisms of exosome-mediated immune evasion and therapeutic resistance in LC, and highlights their key translational implications for clinical application.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112452"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316574","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}
Pub Date : 2026-06-01Epub Date: 2026-02-12DOI: 10.1016/j.cellsig.2026.112387
Tonglong Hu , Miaoheng Yan , Yangyang Chen , Songfeng Chen , Zongmian Song , Xiaobo Jing , Binwu Hu , Hongjian Liu
Programmed cell death, particularly pyroptosis mediated by inflammatory signaling pathways, plays a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). However, the regulatory mechanisms underlying pyroptosis and inflammation in IVDD remain poorly understood. Voltage-dependent anion channel 1 (VDAC1), a pivotal mitochondrial protein, forms oligomeric structures under inflammatory stimulation, leading to mitochondrial DNA (mtDNA) release into the cytoplasm and extracellular space. This triggers inflammatory cascades and activates pyroptosis signaling pathways, yet its physiological role and regulatory mechanisms in IVDD are still unclear. In this study, we demonstrated that the expression of VDAC1 was increased in degenerated NP tissues, and oxidative stress induced the expression and oligomerization of VDAC1 in NPC. Inhibiting VDAC1 by specific inhibitor NSC15364 or downregulating the expression of VDAC1 by specific siRNAs attenuated the mitochondrial dysfunction and pyroptosis of NPC. Mechanistically, we proved that inhibiting VDAC1 alleviated the cytosolic leakage of mtDNA, which subsequently blocked the TLR9 signaling pathway, ultimately alleviating the pyroptosis of NPC in vitro and in vivo. Our results proved for the first time that VDAC1-mtDNA-TLR9 signaling pathway might be a novel target for the treatment of IVDD.
{"title":"VDAC1-mediated cytosolic leakage of mtDNA triggers pyroptosis of nucleus pulposus cells by activating the TLR9 signaling pathway","authors":"Tonglong Hu , Miaoheng Yan , Yangyang Chen , Songfeng Chen , Zongmian Song , Xiaobo Jing , Binwu Hu , Hongjian Liu","doi":"10.1016/j.cellsig.2026.112387","DOIUrl":"10.1016/j.cellsig.2026.112387","url":null,"abstract":"<div><div>Programmed cell death, particularly pyroptosis mediated by inflammatory signaling pathways, plays a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). However, the regulatory mechanisms underlying pyroptosis and inflammation in IVDD remain poorly understood. Voltage-dependent anion channel 1 (VDAC1), a pivotal mitochondrial protein, forms oligomeric structures under inflammatory stimulation, leading to mitochondrial DNA (mtDNA) release into the cytoplasm and extracellular space. This triggers inflammatory cascades and activates pyroptosis signaling pathways, yet its physiological role and regulatory mechanisms in IVDD are still unclear. In this study, we demonstrated that the expression of VDAC1 was increased in degenerated NP tissues, and oxidative stress induced the expression and oligomerization of VDAC1 in NPC. Inhibiting VDAC1 by specific inhibitor NSC15364 or downregulating the expression of VDAC1 by specific siRNAs attenuated the mitochondrial dysfunction and pyroptosis of NPC. Mechanistically, we proved that inhibiting VDAC1 alleviated the cytosolic leakage of mtDNA, which subsequently blocked the TLR9 signaling pathway, ultimately alleviating the pyroptosis of NPC in vitro and in vivo. Our results proved for the first time that VDAC1-mtDNA-TLR9 signaling pathway might be a novel target for the treatment of IVDD.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112387"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172400","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}
Pub Date : 2026-06-01Epub Date: 2026-02-05DOI: 10.1016/j.cellsig.2026.112398
Tianbao Song , Wenlin He , Qin Yuan , Sihan Xia, Qin Yi, Yipeng He, Weimin Yu, Fan Cheng
Tumor-associated fibroblast-mediated matrix remodeling is an important feature of invasive immune-rejection bladder cancer, but its pathogenic mechanism and potential therapeutic targets are still unclear. The matrix and immune interaction network and core related genes in bladder cancer were systematically investigated by combining single-cell transcriptome data analysis and fibroblast GWAS data with TCGA and GEO data deconvolution, WGCNA, drug response prediction, multiplex immunofluorescence, and in vitro and in vivo validation experiments of cells and animals. ADAM12's functional validation. The findings demonstrated that the tumor-associated fibroblast ECM-CAF subgroup infiltration was evident in bladder cancer and was substantially associated with the upregulation of the core genes ADAM12 and TP53-biased basal-like program. These were characterized by the deposition of dense matrix, the upregulation of numerous immune checkpoints, the rejection and dysfunction of T cells, and a decrease in immunogenicity. Multiplex immunofluorescence localization of bladder cancer and normal bladder tissue showed that ADAM12 was significantly associated with the progression of non-muscle invasive bladder cancer to muscle invasive bladder cancer and the infiltration of ECM-CAF. Knockdown of ADAM12 inhibited the proliferation, migration, and invasion of bladder cancer cells, reduced the activation of the PI3K–AKT–mTOR pathway, and inhibited bladder cancer xenograft growth and lung metastasis. ADAM12 overexpression triggered the PI3K–AKT–mTOR pathway, enhanced the development and lung metastasis of bladder cancer xenografts, and markedly increased the invasion, migration, and proliferation of bladder cancer cells. The above results indicate that ADAM12, as a matrix-driven factor, links matrix remodeling, PI3K-AKT signaling pathway and bladder cancer immunosuppression, and has good prognostic and therapeutic stratification potential, providing new ideas for precision targeted intervention and treatment of bladder cancer.
{"title":"ADAM12-programmed ECM-CAF remodeling activates PI3K–AKT and enforces an immune-excluded microenvironment to drive bladder cancer progression and therapy resistance","authors":"Tianbao Song , Wenlin He , Qin Yuan , Sihan Xia, Qin Yi, Yipeng He, Weimin Yu, Fan Cheng","doi":"10.1016/j.cellsig.2026.112398","DOIUrl":"10.1016/j.cellsig.2026.112398","url":null,"abstract":"<div><div>Tumor-associated fibroblast-mediated matrix remodeling is an important feature of invasive immune-rejection bladder cancer, but its pathogenic mechanism and potential therapeutic targets are still unclear. The matrix and immune interaction network and core related genes in bladder cancer were systematically investigated by combining single-cell transcriptome data analysis and fibroblast GWAS data with TCGA and GEO data deconvolution, WGCNA, drug response prediction, multiplex immunofluorescence, and in vitro and in vivo validation experiments of cells and animals. ADAM12's functional validation. The findings demonstrated that the tumor-associated fibroblast ECM-CAF subgroup infiltration was evident in bladder cancer and was substantially associated with the upregulation of the core genes ADAM12 and TP53-biased basal-like program. These were characterized by the deposition of dense matrix, the upregulation of numerous immune checkpoints, the rejection and dysfunction of T cells, and a decrease in immunogenicity. Multiplex immunofluorescence localization of bladder cancer and normal bladder tissue showed that ADAM12 was significantly associated with the progression of non-muscle invasive bladder cancer to muscle invasive bladder cancer and the infiltration of ECM-CAF. Knockdown of ADAM12 inhibited the proliferation, migration, and invasion of bladder cancer cells, reduced the activation of the PI3K–AKT–mTOR pathway, and inhibited bladder cancer xenograft growth and lung metastasis. ADAM12 overexpression triggered the PI3K–AKT–mTOR pathway, enhanced the development and lung metastasis of bladder cancer xenografts, and markedly increased the invasion, migration, and proliferation of bladder cancer cells. The above results indicate that ADAM12, as a matrix-driven factor, links matrix remodeling, PI3K-AKT signaling pathway and bladder cancer immunosuppression, and has good prognostic and therapeutic stratification potential, providing new ideas for precision targeted intervention and treatment of bladder cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112398"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131447","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}
Pub Date : 2026-06-01Epub Date: 2026-02-12DOI: 10.1016/j.cellsig.2026.112429
Xuhong Zhang , Tian Tian , Ping Cao , Xiaohong Ma , Yinjuan Liu , Xueqin Ding , Xiaoming Yang
Elevated homocysteine (Hcy) levels are well established as an independent risk factor for atherosclerosis and its associated cardiovascular diseases. Macrophage pyroptosis- mediated inflammation plays a crucial role in the progression of atherosclerosis. Notably, glycoprotein non-metastatic melanoma protein B (GPNMB) expression is increased in macrophages within atherosclerotic plaques; however, whether GPNMB participates in Hcy-induced macrophage pyroptosis remains elusive. In the present study, we found that GPNMB expression was upregulated in Hcy- treated THP-1- derived macrophages. Consistently, serum GPNMB levels were significantly higher in patients with hyperhomocysteinemia (HHcy) compared with healthy controls. Functional experiments showed that silencing GPNMB reduced Hcy-triggered pyroptosis in THP-1-derived macrophages, whereas GPNMB overexpression exerted the opposite effect. Mechanistically, GPNMB upregulated the NOX2/NF-κB signaling pathway in THP-1-derived macrophages. Importantly, the pro-pyroptotic effect of GPNMB overexpression in Hcy-treated THP-1-derived macrophages was counteracted by either inhibition of NADPH oxidase 2 (NOX2) using the specific inhibitor gp91ds-tat or blockade of NF-κB activation with the inhibitor BAY11–7082.
Moreover, serum GPNMB levels were correlated with serum Hcy levels and lipid profiles in both healthy individuals and HHcy patients. Collectively, these findings demonstrate that GPNMB facilitates Hcy-induced macrophage pyroptosis associated with the upregulation of the NOX2/NF-κB signaling pathway, highlighting the potential relevance of GPNMB as a candidate target for the clinical management of HHcy-related atherosclerotic cardiovascular disease.
{"title":"Glycoprotein non-metastatic melanoma protein B promotes pyroptosis of macrophages induced by homocysteine associated with the upregulation of the NOX-2/ NF-κB signaling pathway","authors":"Xuhong Zhang , Tian Tian , Ping Cao , Xiaohong Ma , Yinjuan Liu , Xueqin Ding , Xiaoming Yang","doi":"10.1016/j.cellsig.2026.112429","DOIUrl":"10.1016/j.cellsig.2026.112429","url":null,"abstract":"<div><div>Elevated homocysteine (Hcy) levels are well established as an independent risk factor for atherosclerosis and its associated cardiovascular diseases. Macrophage pyroptosis- mediated inflammation plays a crucial role in the progression of atherosclerosis. Notably, glycoprotein non-metastatic melanoma protein B (GPNMB) expression is increased in macrophages within atherosclerotic plaques; however, whether GPNMB participates in Hcy-induced macrophage pyroptosis remains elusive. In the present study, we found that GPNMB expression was upregulated in Hcy- treated THP-1- derived macrophages. Consistently, serum GPNMB levels were significantly higher in patients with hyperhomocysteinemia (HHcy) compared with healthy controls. Functional experiments showed that silencing GPNMB reduced Hcy-triggered pyroptosis in THP-1-derived macrophages, whereas GPNMB overexpression exerted the opposite effect. Mechanistically, GPNMB upregulated the NOX2/NF-κB signaling pathway in THP-1-derived macrophages. Importantly, the pro-pyroptotic effect of GPNMB overexpression in Hcy-treated THP-1-derived macrophages was counteracted by either inhibition of NADPH oxidase 2 (NOX2) using the specific inhibitor gp91ds-tat or blockade of NF-κB activation with the inhibitor BAY11–7082.</div><div>Moreover, serum GPNMB levels were correlated with serum Hcy levels and lipid profiles in both healthy individuals and HHcy patients. Collectively, these findings demonstrate that GPNMB facilitates Hcy-induced macrophage pyroptosis associated with the upregulation of the NOX2/NF-κB signaling pathway, highlighting the potential relevance of GPNMB as a candidate target for the clinical management of HHcy-related atherosclerotic cardiovascular disease.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112429"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197337","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}
Pub Date : 2026-06-01Epub Date: 2026-02-12DOI: 10.1016/j.cellsig.2026.112412
Xintao Hu , Xiaoqing Li , Jichong Chen , Yang Li , Zhao Zhao , Xiangyang Yin , Shichao Duan , Bing Wang
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE−/− mouse model of carotid atherosclerosis via high-fat diet feeding combined with surgical intervention, with thickened fibrous caps, reduced lipid deposition and decreased immune cell infiltration. These protective effects were abolished upon co-administration of SB431542. Immunofluorescence and western blot analyses of clinical samples corroborated that AMIGO1 enhances carotid plaque stability by upregulating TGFRII level. Our collective data indicated that AMIGO1 regulated stability of plaque by promoting endothelial cell adhesion and downregulating inflammatory cytokines production through activating TGFβ/SMAD pathway via interacting with TGFRII. This study provides a critical theoretical foundation for developing clinical therapies and novel targets for CAS.
{"title":"Adhesion molecule with Ig-like domain 1 regulates stability of carotid plaque via TGFβ/Smad signaling pathway by interaction with TGFRII","authors":"Xintao Hu , Xiaoqing Li , Jichong Chen , Yang Li , Zhao Zhao , Xiangyang Yin , Shichao Duan , Bing Wang","doi":"10.1016/j.cellsig.2026.112412","DOIUrl":"10.1016/j.cellsig.2026.112412","url":null,"abstract":"<div><div>Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (<em>n</em> = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE<sup>−</sup>/<sup>−</sup> mouse model of carotid atherosclerosis via high-fat diet feeding combined with surgical intervention, with thickened fibrous caps, reduced lipid deposition and decreased immune cell infiltration. These protective effects were abolished upon co-administration of SB431542. Immunofluorescence and western blot analyses of clinical samples corroborated that AMIGO1 enhances carotid plaque stability by upregulating TGFRII level. Our collective data indicated that AMIGO1 regulated stability of plaque by promoting endothelial cell adhesion and downregulating inflammatory cytokines production through activating TGFβ/SMAD pathway via interacting with TGFRII. This study provides a critical theoretical foundation for developing clinical therapies and novel targets for CAS.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112412"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197187","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}
Pub Date : 2026-06-01Epub Date: 2026-02-28DOI: 10.1016/j.cellsig.2026.112454
Xiangyang He , Qianqian Yang , Xiaowen Lin , Ziyuan Chen , Kaixuan Ren , Jiao Yang , Xiaoqin An , Shangzhu Yang , Li Yang , Qian Xue , Xi Chen , Yuan Wang , Guifang Yu , Ding Yan , Xin Chen
Polyunsaturated fatty acids (PUFAs) have demonstrated promising anticancer properties by inducing cancer cell death and inhibiting cancer metastasis. As dynamic organelles, lipid droplets (LDs) may protect cells from PUFA-induced lipotoxicity by sequestering excess fatty acids. However, the underlying mechanisms regulating LDs dynamics in PUFA-mediated tumor cytotoxicity remain poorly understood. In this study, we report that inhibition of LDs synthesis enhances PUFA-induced cancer cell death, suggesting that LDs formation protects against PUFA cytotoxicity. We further demonstrate that copper ions potentiate the antitumor effects of PUFAs across multiple cancer cell lines primarily by promoting apoptosis rather than cuproptosis or ferroptosis. Mechanistically, copper ions significantly reduce intracellular LDs accumulation by promoting LDs degradation via activation of ATGL-dependent lipophagy. Collectively, these findings uncover a novel mechanism whereby copper ions enhance PUFA-induced tumor cell death through promoting lipophagy, which provides valuable insights for optimizing PUFA-based cancer therapies by targeting lipid metabolism and copper homeostasis.
{"title":"Copper potentiates PUFA-mediated antitumor activity by activating Lipophagy","authors":"Xiangyang He , Qianqian Yang , Xiaowen Lin , Ziyuan Chen , Kaixuan Ren , Jiao Yang , Xiaoqin An , Shangzhu Yang , Li Yang , Qian Xue , Xi Chen , Yuan Wang , Guifang Yu , Ding Yan , Xin Chen","doi":"10.1016/j.cellsig.2026.112454","DOIUrl":"10.1016/j.cellsig.2026.112454","url":null,"abstract":"<div><div>Polyunsaturated fatty acids (PUFAs) have demonstrated promising anticancer properties by inducing cancer cell death and inhibiting cancer metastasis. As dynamic organelles, lipid droplets (LDs) may protect cells from PUFA-induced lipotoxicity by sequestering excess fatty acids. However, the underlying mechanisms regulating LDs dynamics in PUFA-mediated tumor cytotoxicity remain poorly understood. In this study, we report that inhibition of LDs synthesis enhances PUFA-induced cancer cell death, suggesting that LDs formation protects against PUFA cytotoxicity. We further demonstrate that copper ions potentiate the antitumor effects of PUFAs across multiple cancer cell lines primarily by promoting apoptosis rather than cuproptosis or ferroptosis. Mechanistically, copper ions significantly reduce intracellular LDs accumulation by promoting LDs degradation via activation of ATGL-dependent lipophagy. Collectively, these findings uncover a novel mechanism whereby copper ions enhance PUFA-induced tumor cell death through promoting lipophagy, which provides valuable insights for optimizing PUFA-based cancer therapies by targeting lipid metabolism and copper homeostasis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112454"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324132","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}
Pub Date : 2026-06-01Epub Date: 2026-02-03DOI: 10.1016/j.cellsig.2026.112406
Sijun Liu , Shasha Tu , Mengmeng Duan , Jiazhou Li , Li Zhang , Jie Ren , Ting Zhao , Jing Xie , Xiaoheng Liu
Osteoclasts function as the primary effectors of bone resorption and are essential for bone homeostasis. Krüppel-like factor 2 (KLF2) has been implicated in osteoclast differentiation, but its precise mechanism remains poorly understood. In this study, we aimed to investigate the role of KLF2 in osteoclast function by characterising osteoclastogenesis, maturation and activity and to explore the underlying biomechanism. We showed that KLF2 negatively regulates osteoclastogenesis by characterising the osteoclast number, size and protein markers; that it negatively regulates osteoclast maturation by characterising the formation of intact actin rings and punctured podosome clusters; and that it negatively regulates osteoclast activity by characterising intracellular acidification through KLF2 overexpression by lentiviral transfection and KLF2 knockdown by small interfering RNA (siRNA) transfection. The results of chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays revealed that KLF2 directly interacted with c-Fos and c-Jun, which together constitute the activator protein-1 (AP-1) complex. By overexpressing KLF2 and knockdown with si-KLF2, we revealed that KLF2 mediated osteoclast function via negative regulation of the AP-1 complex. The inhibition of AP-1 activity confirmed its importance in KLF2-mediated osteoclast differentiation; Moreover, the inhibition of JNK signalling decreased the AP-1 activation induced by KLF2 knockdown, indicating the importance of the RANKL–MAPK–AP-1–NFATc1 axis in KLF2-regulated osteoclast differentiation. This study reveals a typical type of negative regulation of osteoclasts by KLF2 and provides information for potential therapeutic targets in osteolytic diseases, including osteoporosis.
{"title":"KLF2 interacts with AP-1 to negatively affect osteoclast differentiation and activity","authors":"Sijun Liu , Shasha Tu , Mengmeng Duan , Jiazhou Li , Li Zhang , Jie Ren , Ting Zhao , Jing Xie , Xiaoheng Liu","doi":"10.1016/j.cellsig.2026.112406","DOIUrl":"10.1016/j.cellsig.2026.112406","url":null,"abstract":"<div><div>Osteoclasts function as the primary effectors of bone resorption and are essential for bone homeostasis. Krüppel-like factor 2 (KLF2) has been implicated in osteoclast differentiation, but its precise mechanism remains poorly understood. In this study, we aimed to investigate the role of KLF2 in osteoclast function by characterising osteoclastogenesis, maturation and activity and to explore the underlying biomechanism. We showed that KLF2 negatively regulates osteoclastogenesis by characterising the osteoclast number, size and protein markers; that it negatively regulates osteoclast maturation by characterising the formation of intact actin rings and punctured podosome clusters; and that it negatively regulates osteoclast activity by characterising intracellular acidification through KLF2 overexpression by lentiviral transfection and KLF2 knockdown by small interfering RNA (siRNA) transfection. The results of chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays revealed that KLF2 directly interacted with c-Fos and c-Jun, which together constitute the activator protein-1 (AP-1) complex. By overexpressing KLF2 and knockdown with si-KLF2, we revealed that KLF2 mediated osteoclast function <em>via</em> negative regulation of the AP-1 complex. The inhibition of AP-1 activity confirmed its importance in KLF2-mediated osteoclast differentiation; Moreover, the inhibition of JNK signalling decreased the AP-1 activation induced by KLF2 knockdown, indicating the importance of the RANKL–MAPK–AP-1–NFATc1 axis in KLF2-regulated osteoclast differentiation. This study reveals a typical type of negative regulation of osteoclasts by KLF2 and provides information for potential therapeutic targets in osteolytic diseases, including osteoporosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112406"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123887","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}
Pub Date : 2026-06-01Epub Date: 2026-02-05DOI: 10.1016/j.cellsig.2026.112413
Diego Elias Montoya-Durango , Leila Gobejishvili
Liver disease is a global health problem responsible for more than two million deaths annually. Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are major contributors to chronic liver disease-related morbidity and mortality. Factors like diet and alcohol consumption have become key drivers of liver pathologies including steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma. To date very few treatments are available, hence there is a critical need for the development of novel therapies to slow down the development/progression of liver damage. The long non-coding RNA H19 gene, H19, is an imprinted gene normally expressed from the maternally inherited chromosome and epigenetically silenced in the paternal chromosome. At the embryo stage H19 controls genome-wide methylation, directs the methylation of the imprinted gene network, and regulates organ size. In the livers of neonates, H19 is important for organ maturation but remains silent in the mature organ. H19 re-expression in the adult liver drives de novo lipogenesis and fibrosis and maintains a proliferative state in tumor cells. The complexity of H19 functions in the liver is reflected in its interaction and regulation of a growing number of proteins, and coding and non-coding RNAs involved in metabolism, pro-fibrotic gene networks, cell cycle progression, and chromatin regulation. This review summarizes the findings related to the role of H19 in liver development and in diseases such as fatty liver, fibrosis, and hepatocellular carcinoma.
{"title":"Long noncoding RNA H19 in liver development and disease","authors":"Diego Elias Montoya-Durango , Leila Gobejishvili","doi":"10.1016/j.cellsig.2026.112413","DOIUrl":"10.1016/j.cellsig.2026.112413","url":null,"abstract":"<div><div>Liver disease is a global health problem responsible for more than two million deaths annually. Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are major contributors to chronic liver disease-related morbidity and mortality. Factors like diet and alcohol consumption have become key drivers of liver pathologies including steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma. To date very few treatments are available, hence there is a critical need for the development of novel therapies to slow down the development/progression of liver damage. The long non-coding RNA H19 gene, H19, is an imprinted gene normally expressed from the maternally inherited chromosome and epigenetically silenced in the paternal chromosome. At the embryo stage H19 controls genome-wide methylation, directs the methylation of the imprinted gene network, and regulates organ size. In the livers of neonates, H19 is important for organ maturation but remains silent in the mature organ. H19 re-expression in the adult liver drives <em>de novo</em> lipogenesis and fibrosis and maintains a proliferative state in tumor cells. The complexity of H19 functions in the liver is reflected in its interaction and regulation of a growing number of proteins, and coding and non-coding RNAs involved in metabolism, pro-fibrotic gene networks, cell cycle progression, and chromatin regulation. This review summarizes the findings related to the role of H19 in liver development and in diseases such as fatty liver, fibrosis, and hepatocellular carcinoma.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"142 ","pages":"Article 112413"},"PeriodicalIF":3.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137208","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}
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