Pub Date : 2026-01-09DOI: 10.1016/j.cellsig.2026.112360
Xiuchun Zhang , Jianying Feng , Jie Zhou , Jian Wang , Yang Yang
Nonalcoholic fatty liver disease (NAFLD) represents the most prevalent chronic liver disease, yet there remains an unmet need for effective therapeutic interventions. This study aimed to investigate the hepatoprotective effect of Ophiopogonis japonicus polysaccharides (OJPs) on NAFLD and its mechanism. The benefits of OJPs or the positive drug fenofibrate in NAFLD were assessed in mice fed a high-fat diet (HFD). AML12 cells were induced with PA/OA to construct an in vitro model, and the benefits of OJPs were assessed in terms of oil red O staining, BODIPY staining, changes in the expression of lipid accumulation-related proteins, iron metabolism-related proteins, and oxidative stress analysis. OJPs significantly alleviated lipid accumulation and oxidative stress in PA/OA-induced AML12 cells, and maintained iron metabolism in the liver of HFD-induced mice, but the benefits of OJPs were reversed after exogenous inhibition of Runt-related transcription factor 3 (Runx3). More importantly, knockdown of Runx3 combined with overexpression of ATP-binding cassette transporter 7 (Abcb7) again restored the benefit of OJPs. Runx3 transcriptionally activated Abcb7 by binding to its promoter. The findings suggest that OJPs could serve as a pharmaceutical intervention for NAFLD through the Runx3/Abcb7 axis. This discovery unveils an unexplored association between iron metabolism and hepatic disease.
{"title":"Ophiopogonis japonicus polysaccharide inhibits oxidative stress in hepatocytes by promoting Runx3 in nonalcoholic fatty liver disease","authors":"Xiuchun Zhang , Jianying Feng , Jie Zhou , Jian Wang , Yang Yang","doi":"10.1016/j.cellsig.2026.112360","DOIUrl":"10.1016/j.cellsig.2026.112360","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD) represents the most prevalent chronic liver disease, yet there remains an unmet need for effective therapeutic interventions. This study aimed to investigate the hepatoprotective effect of Ophiopogonis japonicus polysaccharides (OJPs) on NAFLD and its mechanism. The benefits of OJPs or the positive drug fenofibrate in NAFLD were assessed in mice fed a high-fat diet (HFD). AML12 cells were induced with PA/OA to construct an <em>in vitro</em> model, and the benefits of OJPs were assessed in terms of oil red O staining, BODIPY staining, changes in the expression of lipid accumulation-related proteins, iron metabolism-related proteins, and oxidative stress analysis. OJPs significantly alleviated lipid accumulation and oxidative stress in PA/OA-induced AML12 cells, and maintained iron metabolism in the liver of HFD-induced mice, but the benefits of OJPs were reversed after exogenous inhibition of Runt-related transcription factor 3 (<em>Runx3)</em>. More importantly, knockdown of <em>Runx3</em> combined with overexpression of ATP-binding cassette transporter 7 (<em>Abcb7)</em> again restored the benefit of OJPs. Runx3 transcriptionally activated <em>Abcb7</em> by binding to its promoter. The findings suggest that OJPs could serve as a pharmaceutical intervention for NAFLD through the Runx3/Abcb7 axis. This discovery unveils an unexplored association between iron metabolism and hepatic disease.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112360"},"PeriodicalIF":3.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951581","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 : 2026-01-09DOI: 10.1016/j.cellsig.2026.112359
Tao Shu , Ning Luo , Yuqi Shu , Jingyan Wei , Hongxin Niu , Qicai Liu
Renal fibrosis is a primary pathological feature of chronic kidney disease, with a current lack of effective treatments. In this study, we observed that Limb-bud and Heart (LBH) expression was upregulated in kidney specimens obtained from patients with chronic kidney disease. During UUO-induced renal fibrosis, both the protein level and mRNA level of LBH were significantly elevated. Furthermore, knockout of the mouse LBH gene significantly ameliorated renal fibrosis. The application of inhibitors, agonists, and knockout mouse models uniformly verified the role of LBH deficiency in alleviating both endoplasmic reticulum stress (ERS) and pyroptosis. Although renal tubular epithelial cells (RTECs) are conventionally considered the initial responders to renal fibrosis, the role and mechanism of LBH in these cells during disease progression remain unclear. Therefore, this study focused on investigating LBH's effects in damaged RTECs. Mechanistic studies demonstrated that within renal tubular epithelial cells, LBH significantly promotes renal fibrosis by forming a positive feedback loop with TGFβ1 and ERS. This activated ERS subsequently further induces pyroptosis and partial epithelial-mesenchymal transition (pEMT), thereby promoting renal fibrosis. Importantly, LBH deficiency was shown to significantly attenuate renal fibrosis. These collective findings strongly suggest that LBH may constitute a promising therapeutic target for the treatment of renal fibrosis.
{"title":"The Limb-bud and Heart (LBH) promotes renal fibrosis through endoplasmic reticulum stress-induced pyroptosis and partial epithelial-mesenchymal transition in renal tubular epithelial cells","authors":"Tao Shu , Ning Luo , Yuqi Shu , Jingyan Wei , Hongxin Niu , Qicai Liu","doi":"10.1016/j.cellsig.2026.112359","DOIUrl":"10.1016/j.cellsig.2026.112359","url":null,"abstract":"<div><div>Renal fibrosis is a primary pathological feature of chronic kidney disease, with a current lack of effective treatments. In this study, we observed that Limb-bud and Heart (LBH) expression was upregulated in kidney specimens obtained from patients with chronic kidney disease. During UUO-induced renal fibrosis, both the protein level and mRNA level of LBH were significantly elevated. Furthermore, knockout of the mouse LBH gene significantly ameliorated renal fibrosis. The application of inhibitors, agonists, and knockout mouse models uniformly verified the role of LBH deficiency in alleviating both endoplasmic reticulum stress (ERS) and pyroptosis. Although renal tubular epithelial cells (RTECs) are conventionally considered the initial responders to renal fibrosis, the role and mechanism of LBH in these cells during disease progression remain unclear. Therefore, this study focused on investigating LBH's effects in damaged RTECs. Mechanistic studies demonstrated that within renal tubular epithelial cells, LBH significantly promotes renal fibrosis by forming a positive feedback loop with TGFβ1 and ERS. This activated ERS subsequently further induces pyroptosis and partial epithelial-mesenchymal transition (pEMT), thereby promoting renal fibrosis. Importantly, LBH deficiency was shown to significantly attenuate renal fibrosis. These collective findings strongly suggest that LBH may constitute a promising therapeutic target for the treatment of renal fibrosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112359"},"PeriodicalIF":3.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951538","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 : 2026-01-09DOI: 10.1016/j.cellsig.2026.112362
Xianglian Wang , Jia He , Simeng Shen , Manwei Li , Siyi Yuan , Wei Xu , Shu Zhu , Yan Ding , Xiuli Wang
Fibrosis is a defining feature of endometriosis (EMS). Our previous single-cell RNA sequencing (scRNA-seq) revealed myofibroblasts (MFBs) as the predominant cells in ectopic endometrium (ECE), mainly derived from fibroblast-to-myofibroblast transition (FMT) driven by transforming growth factor (TGF)-β pathways. Insulin-like growth factor binding proteins (IGFBPs), known regulators of fibrosis in other diseases, remain unexplored in EMS. This study investigated the role of IGFBPs in TGF-β1-induced FMT during EMS-associated fibrosis. We found that elevated TGF-β1 and TGF-βR1 in the EMS microenvironment promoted MFB formation via Smad2/3 and ERK1/2 signaling. IGFBP1 and IGFBP2 were upregulated, whereas IGFBP6 was downregulated in ectopic endometrial stromal cells (EcESCs), and all interacted with TGF-β1. Importantly, IGFBP6 suppressed TGF-β1-induced FMT and fibrosis. This is the first study to define the role of IGFBPs in EMS fibrosis, highlighting IGFBP6 as a potential antifibrotic factor and therapeutic target.
{"title":"The role of insulin-like growth factor binding proteins in TGF-β1-induced fibroblast-myofibroblast transition during endometriosis fibrosis","authors":"Xianglian Wang , Jia He , Simeng Shen , Manwei Li , Siyi Yuan , Wei Xu , Shu Zhu , Yan Ding , Xiuli Wang","doi":"10.1016/j.cellsig.2026.112362","DOIUrl":"10.1016/j.cellsig.2026.112362","url":null,"abstract":"<div><div>Fibrosis is a defining feature of endometriosis (EMS). Our previous single-cell RNA sequencing (scRNA-seq) revealed myofibroblasts (MFBs) as the predominant cells in ectopic endometrium (ECE), mainly derived from fibroblast-to-myofibroblast transition (FMT) driven by transforming growth factor (TGF)-β pathways. Insulin-like growth factor binding proteins (IGFBPs), known regulators of fibrosis in other diseases, remain unexplored in EMS. This study investigated the role of IGFBPs in TGF-β1-induced FMT during EMS-associated fibrosis. We found that elevated TGF-β1 and TGF-βR1 in the EMS microenvironment promoted MFB formation via Smad2/3 and ERK1/2 signaling. IGFBP1 and IGFBP2 were upregulated, whereas IGFBP6 was downregulated in ectopic endometrial stromal cells (EcESCs), and all interacted with TGF-β1. Importantly, IGFBP6 suppressed TGF-β1-induced FMT and fibrosis. This is the first study to define the role of IGFBPs in EMS fibrosis, highlighting IGFBP6 as a potential antifibrotic factor and therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112362"},"PeriodicalIF":3.7,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948026","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 : 2026-01-08DOI: 10.1016/j.cellsig.2026.112355
Yuchen Ma , Jiaming Wu , HaoRan Zhao , WeiWang Fan , QinYun Wang , Xiaoxiao Zhuang , LiYing Zhang , Xinchen Zhang
Ferroptosis is an iron-dependent, non-apoptotic form of cell death induced by the accumulation of lipid peroxidation products. It is involved in cisplatin-induced tumor cell death and plays a dual role of “synergistic enhancement” and “resistance regulation”. Furthermore, ferroptosis enhances anti-tumor activity through mechanisms similar to those of cisplatin. Activation of the ferroptosis defence system in tumor cells may cause cisplatin resistance. Cisplatin is a first-line chemotherapeutic agent for intrahepatic cholangiocarcinoma (ICC); however, drug resistance impairs its efficacy. Therefore, exploring ferroptosis-related factors in ICC may help address cisplatin resistance. Moreover, these factors may serve as novel therapeutic targets. We identified BTB and CNC homology 1 (BACH1) by integrating The Cancer Genome Atlas and Ferroptosis Database datasets. BACH1 is upregulated in ICC and associated with poor prognosis. It promotes ICC progression and binds t lactate dehydrogenase A and monocarboxylate transporter 4 promoters to enhance lactate metabolism. Lactate, a crucial downstream effector, can impede ferroptosis through various mechanisms, such as modulating intracellular iron levels, boosting antioxidant system efficacy, and repressing key ferroptosis executor molecules. Additional investigations confirm that BACH1 specifically mitigates cisplatin-triggered tumor cell death by regulating the “BACH1-LDHA/McT4-lactate metabolism-ferroptosis inhibition” axis, leading to cisplatin resistance in ICC cells. Our findings revealed that through this regulatory axis, BACH1 induces cisplatin resistance and may serve as a therapeutic target in ICC.
{"title":"BACH1 promotes lactate metabolism by transcriptionally upregulating LDHA and MCT4 expression to inhibit ferroptosis in intrahepatic cholangiocarcinoma cells","authors":"Yuchen Ma , Jiaming Wu , HaoRan Zhao , WeiWang Fan , QinYun Wang , Xiaoxiao Zhuang , LiYing Zhang , Xinchen Zhang","doi":"10.1016/j.cellsig.2026.112355","DOIUrl":"10.1016/j.cellsig.2026.112355","url":null,"abstract":"<div><div>Ferroptosis is an iron-dependent, non-apoptotic form of cell death induced by the accumulation of lipid peroxidation products. It is involved in cisplatin-induced tumor cell death and plays a dual role of “synergistic enhancement” and “resistance regulation”. Furthermore, ferroptosis enhances anti-tumor activity through mechanisms similar to those of cisplatin. Activation of the ferroptosis defence system in tumor cells may cause cisplatin resistance. Cisplatin is a first-line chemotherapeutic agent for intrahepatic cholangiocarcinoma (ICC); however, drug resistance impairs its efficacy. Therefore, exploring ferroptosis-related factors in ICC may help address cisplatin resistance. Moreover, these factors may serve as novel therapeutic targets. We identified BTB and CNC homology 1 (BACH1) by integrating The Cancer Genome Atlas and Ferroptosis Database datasets. BACH1 is upregulated in ICC and associated with poor prognosis. It promotes ICC progression and binds t lactate dehydrogenase A and monocarboxylate transporter 4 promoters to enhance lactate metabolism. Lactate, a crucial downstream effector, can impede ferroptosis through various mechanisms, such as modulating intracellular iron levels, boosting antioxidant system efficacy, and repressing key ferroptosis executor molecules. Additional investigations confirm that BACH1 specifically mitigates cisplatin-triggered tumor cell death by regulating the “BACH1-LDHA/McT4-lactate metabolism-ferroptosis inhibition” axis, leading to cisplatin resistance in ICC cells. Our findings revealed that through this regulatory axis, BACH1 induces cisplatin resistance and may serve as a therapeutic target in ICC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112355"},"PeriodicalIF":3.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948027","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 : 2026-01-08DOI: 10.1016/j.cellsig.2025.112348
Huan Yuan , Xinyi Guo , Yihao Li , Xiwen Sun , Xinyu Wang , Lutong Zhang , Lei Gao , Chuanjiang Cai , Rui Liu , Guiyan Chu
Reproductive performance is critical for livestock productivity. Ovarian granulosa cells (GCs) play a central role in female reproduction. These cells are involved in follicular development, maturation, and atresia by regulating proliferation, secretion, and apoptosis. Here, we found that interferon alpha inducible protein 6 (IFI6) is highly expressed in estrous gilts compared to anestrous gilts. Functional studies demonstrated that both knockdown and overexpression of IFI6 alters estrogen synthesis, cell proliferation, and apoptosis in granulosa cells. Mechanistically, IFI6 regulates physiological functions via the Phosphoinositide 3-kinase/protein kinase B (PI3K - Akt) signaling pathway. Moreover, the PI3K-Akt signaling pathway activates activator protein 1 (AP - 1). According to ChIP-Atlas data, AP - 1 binding sites are present in the promoters of genes such as CYP19A1, BAX, BCL2, CYCLIN D, and CYCLIN B. Therefore, we propose a model where IFI6 activates the PI3K-Akt pathway, which in turn upregulates AP - 1 to promote estrogen synthesis and cell proliferation while inhibiting apoptosis. These findings identify that IFI6 plays a critical role in the physiological regulation of porcine ovarian granulosa cells. IFI6 could enhance the precision of genomic selection for improving fertility in porcine.
{"title":"IFI6 regulation of physiological functions in granulosa cells","authors":"Huan Yuan , Xinyi Guo , Yihao Li , Xiwen Sun , Xinyu Wang , Lutong Zhang , Lei Gao , Chuanjiang Cai , Rui Liu , Guiyan Chu","doi":"10.1016/j.cellsig.2025.112348","DOIUrl":"10.1016/j.cellsig.2025.112348","url":null,"abstract":"<div><div>Reproductive performance is critical for livestock productivity. Ovarian granulosa cells (GCs) play a central role in female reproduction. These cells are involved in follicular development, maturation, and atresia by regulating proliferation, secretion, and apoptosis. Here, we found that interferon alpha inducible protein 6 (IFI6) is highly expressed in estrous gilts compared to anestrous gilts. Functional studies demonstrated that both knockdown and overexpression of IFI6 alters estrogen synthesis, cell proliferation, and apoptosis in granulosa cells. Mechanistically, IFI6 regulates physiological functions via the Phosphoinositide 3-kinase/protein kinase B (PI3K - Akt) signaling pathway. Moreover, the PI3K-Akt signaling pathway activates activator protein 1 (AP - 1). According to ChIP-Atlas data, AP - 1 binding sites are present in the promoters of genes such as <em>CYP19A1, BAX, BCL2, CYCLIN D</em>, and <em>CYCLIN B</em>. Therefore, we propose a model where IFI6 activates the PI3K-Akt pathway, which in turn upregulates AP - 1 to promote estrogen synthesis and cell proliferation while inhibiting apoptosis. These findings identify that IFI6 plays a critical role in the physiological regulation of porcine ovarian granulosa cells. IFI6 could enhance the precision of genomic selection for improving fertility in porcine.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112348"},"PeriodicalIF":3.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948404","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 : 2026-01-06DOI: 10.1016/j.cellsig.2026.112357
Qian Lu , Ninglin Xia , Jicheng Wang , Yulin Yi , Xue Fan , Ming Jin , Xiaofei Huang , Wenwen Xin , Li Sun , Jinyu Hu , Zhenzhou Jiang , Qinwei Yu
All-trans retinoic acid (ATRA), the active metabolite of vitamin A, serves as the first-line therapy for acute promyelocytic leukemia (APL) in clinical. However, increasing clinical evidence indicates that ATRA treatment is frequently associated with dyslipidemia, the underlying molecular mechanisms of which remain unclear. Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), is widely used in the management of metabolic disorders, yet its potential to alleviate ATRA-induced lipid abnormalities has not been fully elucidated. In this study, we established a mouse model of ATRA-induced hyperlipidemia and hepatic steatosis to investigate the underlying mechanisms and assess the therapeutic effects of fenofibrate as a combinatorial agent. Our findings revealed that ATRA promoted the formation of RARα/RXRα heterodimers, which activated the hepatic FOXO1-APOCIII pathway, leading to hyperlipidemia and hepatic lipid accumulation in mice. Fenofibrate effectively counteracted these effects by activating PPARα, thereby competitively inhibiting RARα binding to RXRα and restoring lipid homeostasis. This study reveals a novel mechanism underlying ATRA-induced hyperlipidemia and hepatic lipid accumulation, which offers a theoretical foundation for the clinical use of fenofibrate in managing ATRA-induced hyperlipidemia and hepatic steatosis.
{"title":"Fenofibrate anti-RARα/RXRα dimerization to attenuate all-trans retinoic acid-induced hyperlipidemia and hepatic steatosis in mice","authors":"Qian Lu , Ninglin Xia , Jicheng Wang , Yulin Yi , Xue Fan , Ming Jin , Xiaofei Huang , Wenwen Xin , Li Sun , Jinyu Hu , Zhenzhou Jiang , Qinwei Yu","doi":"10.1016/j.cellsig.2026.112357","DOIUrl":"10.1016/j.cellsig.2026.112357","url":null,"abstract":"<div><div>All-trans retinoic acid (ATRA), the active metabolite of vitamin A, serves as the first-line therapy for acute promyelocytic leukemia (APL) in clinical. However, increasing clinical evidence indicates that ATRA treatment is frequently associated with dyslipidemia, the underlying molecular mechanisms of which remain unclear. Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), is widely used in the management of metabolic disorders, yet its potential to alleviate ATRA-induced lipid abnormalities has not been fully elucidated. In this study, we established a mouse model of ATRA-induced hyperlipidemia and hepatic steatosis to investigate the underlying mechanisms and assess the therapeutic effects of fenofibrate as a combinatorial agent. Our findings revealed that ATRA promoted the formation of RARα/RXRα heterodimers, which activated the hepatic FOXO1-APOCIII pathway, leading to hyperlipidemia and hepatic lipid accumulation in mice. Fenofibrate effectively counteracted these effects by activating PPARα, thereby competitively inhibiting RARα binding to RXRα and restoring lipid homeostasis. This study reveals a novel mechanism underlying ATRA-induced hyperlipidemia and hepatic lipid accumulation, which offers a theoretical foundation for the clinical use of fenofibrate in managing ATRA-induced hyperlipidemia and hepatic steatosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112357"},"PeriodicalIF":3.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921705","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 : 2026-01-05DOI: 10.1016/j.cellsig.2026.112353
Jing Zhang, Yipeng Dong, Xianghua Zhang, Tao Wu
Despite the documented involvement of neutrophil extracellular traps (NETs) in various cancer types, their specific role in meningioma development remains understudied. Here, we report a mechanism by which the JAM3/Mac-1 interaction promotes meningioma development via NETs. We found that JAM3 knockdown in meningioma cells suppressed AKT phosphorylation, thereby reducing neutrophil migration and NET formation in co-culture; these effects were rescued by the AKT activator SC79. Co-IP confirmed the JAM3/Mac-1 interaction. In a xenograft model, JAM3 knockdown inhibited tumor growth and intratumoral NETs. Furthermore, NETs enhanced meningioma cell growth in vitro and in vivo, an effect abolished by DNase I. Conversely, Mac-1 knockdown in neutrophils impaired their function, which was also restored by SC79. Clinically, JAM3 expression correlated with Mac-1 and NET markers in meningioma samples. In conclusion, JAM3 promotes meningioma development by regulating the formation of NET through the Mac-1/AKT axis. These findings offer novel insights for treating these common primary tumors of the central nervous system.
{"title":"JAM3 orchestrates Mac-1-dependent AKT phosphorylation to facilitate neutrophil extracellular trap-driven meningioma pathogenesis","authors":"Jing Zhang, Yipeng Dong, Xianghua Zhang, Tao Wu","doi":"10.1016/j.cellsig.2026.112353","DOIUrl":"10.1016/j.cellsig.2026.112353","url":null,"abstract":"<div><div>Despite the documented involvement of neutrophil extracellular traps (NETs) in various cancer types, their specific role in meningioma development remains understudied. Here, we report a mechanism by which the JAM3/Mac-1 interaction promotes meningioma development <em>via</em> NETs. We found that JAM3 knockdown in meningioma cells suppressed AKT phosphorylation, thereby reducing neutrophil migration and NET formation in co-culture; these effects were rescued by the AKT activator SC79. Co-IP confirmed the JAM3/Mac-1 interaction. In a xenograft model, JAM3 knockdown inhibited tumor growth and intratumoral NETs. Furthermore, NETs enhanced meningioma cell growth <em>in vitro</em> and <em>in vivo</em>, an effect abolished by DNase I. Conversely, Mac-1 knockdown in neutrophils impaired their function, which was also restored by SC79. Clinically, JAM3 expression correlated with Mac-1 and NET markers in meningioma samples. In conclusion, JAM3 promotes meningioma development by regulating the formation of NET through the Mac-1/AKT axis. These findings offer novel insights for treating these common primary tumors of the central nervous system.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112353"},"PeriodicalIF":3.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917144","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 : 2026-01-05DOI: 10.1016/j.cellsig.2026.112356
Liting Bao, Chen Wang, Yiqing He, Wenshu Zhang, Yuejun Fu
microRNAs (miRNAs) are a class of non-coding RNA molecules that regulate biophysiological and biochemical processes by modulating gene expression. miR-7 is widespread and sequence conserved across species. Due to its conserved sequence and the similarity of specific expression sites, the miR-7 family members are of great significance in the study of species evolution. This review focuses on the evolutionary characterization of the miR-7 family and the functional diversity. The miR-7 family is widespread in several species and its mature and precursor sequences are evolutionarily conserved. In invertebrates, miR-7 family members are involved in immune defense, cell development and tissue generation, and metabolic regulation. And in chordates, miR-7 family members can be used as therapeutic targets for diseases, affecting the disease process and drug sensitivity by targeting and regulating multiple genes. miR-7 family members also play important roles in cell development and differentiation and tissue regeneration. Here, we focus on the emerging roles of miR-7 family in these processes by discussing functional differences generated by the old and novel targets, mechanisms identified to mediate or interact with miR-7 family and the most recently unraveled clinical implications of miR-7 family regulatory pathways toward diseases.
{"title":"The miR-7 family: an evolutionary conservation and multifunctional miRNA family","authors":"Liting Bao, Chen Wang, Yiqing He, Wenshu Zhang, Yuejun Fu","doi":"10.1016/j.cellsig.2026.112356","DOIUrl":"10.1016/j.cellsig.2026.112356","url":null,"abstract":"<div><div>microRNAs (miRNAs) are a class of non-coding RNA molecules that regulate biophysiological and biochemical processes by modulating gene expression. miR-7 is widespread and sequence conserved across species. Due to its conserved sequence and the similarity of specific expression sites, the miR-7 family members are of great significance in the study of species evolution. This review focuses on the evolutionary characterization of the miR-7 family and the functional diversity. The miR-7 family is widespread in several species and its mature and precursor sequences are evolutionarily conserved. In invertebrates, miR-7 family members are involved in immune defense, cell development and tissue generation, and metabolic regulation. And in chordates, miR-7 family members can be used as therapeutic targets for diseases, affecting the disease process and drug sensitivity by targeting and regulating multiple genes. miR-7 family members also play important roles in cell development and differentiation and tissue regeneration. Here, we focus on the emerging roles of miR-7 family in these processes by discussing functional differences generated by the old and novel targets, mechanisms identified to mediate or interact with miR-7 family and the most recently unraveled clinical implications of miR-7 family regulatory pathways toward diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112356"},"PeriodicalIF":3.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917224","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 : 2026-01-05DOI: 10.1016/j.cellsig.2026.112352
Jingyuan Chen, Yusi Chen, Wenjie Chen, Yingjie Tan, Tianyu Wang, Yilin Xie, Bingyuan Wang, Jun Luo
Objective
Dipeptidyl peptidase-4 (DPP4)-targeted therapy is widely employed in the therapy of pulmonary diseases, but the role of its H3K4me1 modification in pulmonary arterial hypertension (PAH) disease remains unknown. This study aims to investigate the function of histone methyltransferase SET domain containing 7 (Set7)-mediated monomethylation of histone 3 lysine 4 (H3K4me1) modification of DPP4 in PAH, with the goal of providing new insights for the broader application of DPP4-targeted therapies.
Methods
The PAH mouse model was constructed and intervened with overexpression (oe) or knockdown (sh) of DPP4, sh-Set7, oe-NADPH oxidase 4 (NOX4) or sh-Set7 + erastin. Human pulmonary arterial endothelial cells were induced by hypoxia and treated with sh-DPP4, erastin, oe-DPP4, sh-Set7, oe-NOX4, oe-Set7 or oe-Set7 + ferrostatin-1. The enrichment of H3K4me1 level in the DPP4 promoter region was analyzed by ChIP and dual-luciferase assay. Pulmonary vascular remodeling, fibrosis, and endothelial injury were observed by echocardiography, HE, MASSON, and α-SMA staining. Ferroptosis markers and protein expression were measured using biochemical assay kits, RT-qPCR, WB, immunofluorescence, and transmission electron microscopy.
Results
Silencing DPP4 alleviates pulmonary vascular remodeling, fibrosis, and endothelial injury in PAH mice, reduces cardiac fibrosis and pulmonary inflammation, while improving mitochondrial damage in the lungs and downregulating the level of ferroptosis-related proteins. ChIP assays confirmed increased enrichment of H3K4me1 in the DPP4 promoter region in both hypoxia-induced endothelial cells and lung tissues of PAH mice. Overexpression of Set7 resulted in elevated H3K4me1 enrichment in the DPP4 promoter region and increased NOX4 protein expression. Ferrostatin-1 inhibited the promotion of oe-Set7 in hypoxia-induced endothelial cell injury. Silencing Set7 mitigated hypoxia-induced endothelial cell injury, ferroptosis, and inflammatory responses by downregulating DPP4/NOX4. Erastin reversed the treatment effect of sh-Set7 in PAH mice. Furthermore, Set7 knockdown ameliorated PAH in mice by suppressing DPP4/NOX4-mediated ferroptosis.
Conclusion
The H3K4me1 modification of DPP4 is upregulated in PAH, a process regulated by Set7. Silencing Set7 alleviates PAH by suppressing ferroptosis through the DPP4/NOX4 signaling pathway, offering a novel gene therapy approach for this disease.
{"title":"Set7 regulates ferroptosis in pulmonary arterial hypertension endothelial cells through the DPP4/NOX4 axis mediated by H3K4me1 modification","authors":"Jingyuan Chen, Yusi Chen, Wenjie Chen, Yingjie Tan, Tianyu Wang, Yilin Xie, Bingyuan Wang, Jun Luo","doi":"10.1016/j.cellsig.2026.112352","DOIUrl":"10.1016/j.cellsig.2026.112352","url":null,"abstract":"<div><h3>Objective</h3><div>Dipeptidyl peptidase-4 (DPP4)-targeted therapy is widely employed in the therapy of pulmonary diseases, but the role of its H3K4me1 modification in pulmonary arterial hypertension (PAH) disease remains unknown. This study aims to investigate the function of histone methyltransferase SET domain containing 7 (Set7)-mediated monomethylation of histone 3 lysine 4 (H3K4me1) modification of DPP4 in PAH, with the goal of providing new insights for the broader application of DPP4-targeted therapies.</div></div><div><h3>Methods</h3><div>The PAH mouse model was constructed and intervened with overexpression (oe) or knockdown (sh) of DPP4, sh-Set7, oe-NADPH oxidase 4 (NOX4) or sh-Set7 + erastin. Human pulmonary arterial endothelial cells were induced by hypoxia and treated with sh-DPP4, erastin, oe-DPP4, sh-Set7, oe-NOX4, oe-Set7 or oe-Set7 + ferrostatin-1. The enrichment of H3K4me1 level in the DPP4 promoter region was analyzed by ChIP and dual-luciferase assay. Pulmonary vascular remodeling, fibrosis, and endothelial injury were observed by echocardiography, HE, MASSON, and α-SMA staining. Ferroptosis markers and protein expression were measured using biochemical assay kits, RT-qPCR, WB, immunofluorescence, and transmission electron microscopy.</div></div><div><h3>Results</h3><div>Silencing DPP4 alleviates pulmonary vascular remodeling, fibrosis, and endothelial injury in PAH mice, reduces cardiac fibrosis and pulmonary inflammation, while improving mitochondrial damage in the lungs and downregulating the level of ferroptosis-related proteins. ChIP assays confirmed increased enrichment of H3K4me1 in the DPP4 promoter region in both hypoxia-induced endothelial cells and lung tissues of PAH mice. Overexpression of Set7 resulted in elevated H3K4me1 enrichment in the DPP4 promoter region and increased NOX4 protein expression. Ferrostatin-1 inhibited the promotion of oe-Set7 in hypoxia-induced endothelial cell injury. Silencing Set7 mitigated hypoxia-induced endothelial cell injury, ferroptosis, and inflammatory responses by downregulating DPP4/NOX4. Erastin reversed the treatment effect of sh-Set7 in PAH mice. Furthermore, Set7 knockdown ameliorated PAH in mice by suppressing DPP4/NOX4-mediated ferroptosis.</div></div><div><h3>Conclusion</h3><div>The H3K4me1 modification of DPP4 is upregulated in PAH, a process regulated by Set7. Silencing Set7 alleviates PAH by suppressing ferroptosis through the DPP4/NOX4 signaling pathway, offering a novel gene therapy approach for this disease.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112352"},"PeriodicalIF":3.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917239","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 : 2026-01-04DOI: 10.1016/j.cellsig.2026.112354
Qian Yu , Zilin Liu , Jiangtao Yu , Haoli Ma , Yijie Wang , Feihong Yang , Gang Li , Ling Chen , Cheng Jiang
Objective
Sepsis-induced cardiomyopathy (SICM) is a frequent and life-threatening complication of sepsis, characterized by acute cardiac dysfunction and high mortality, yet no specific therapy is currently available. Cordycepin (COR), a natural bioactive compound, has been reported to exert anti-inflammatory and cardioprotective effects; however, its role and underlying mechanisms in SICM remain unclear.
Methods
SICM was established in mice by intraperitoneal lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP). In vitro, HL-1 cells were treated with cytokine mixtures. COR was administered as a pre-treatment in both models. Cardiac function and myocardial injury were evaluated by echocardiography, histopathology, and biochemical assays. Transcriptome sequencing was performed to identify potential pathways, followed by validation using Western blotting and immunofluorescence. Mitochondrial function and cell death were assessed using CCK-8, flow cytometry, JC-1 staining, MitoTracker labeling, and transmission electron microscopy.
Results
COR markedly attenuated myocardial injury induced by LPS, CLP, and cytokine stimulation. Compared with the model group, COR improved cardiac function, increased 7-day survival, and reduced myocardial inflammatory responses. Transcriptomic profiling implicated PI3K/Akt/mTOR signaling, and subsequent in vivo and in vitro experiments supported pathway activation by COR. Mechanistically, COR restored mitochondrial homeostasis and alleviated oxidative stress, evidenced by decreased ROS and MDA and increased SOD activity, while enhancing mitochondrial membrane potential and ATP production. COR also suppressed cardiomyocyte apoptosis, reflected by reduced Bax expression and decreased ratios of Cleaved Caspase-3/Caspase-3 and Cleaved Caspase-9/Caspase-9, along with increased Bcl-2 expression.
Conclusion
COR mitigates inflammation, oxidative stress, and cardiomyocyte apoptosis in SICM via modulation of the PI3K/Akt/mTOR pathway, thereby attenuating myocardial injury and improving cardiac function. Collectively, these findings indicate that COR may serve as a potential novel therapeutic agent for the management of SICM.
{"title":"Cordycepin alleviates sepsis-induced cardiomyopathy by attenuating mitochondrial oxidative stress and apoptosis through modulation of the PI3K/Akt/mTOR pathway","authors":"Qian Yu , Zilin Liu , Jiangtao Yu , Haoli Ma , Yijie Wang , Feihong Yang , Gang Li , Ling Chen , Cheng Jiang","doi":"10.1016/j.cellsig.2026.112354","DOIUrl":"10.1016/j.cellsig.2026.112354","url":null,"abstract":"<div><h3>Objective</h3><div>Sepsis-induced cardiomyopathy (SICM) is a frequent and life-threatening complication of sepsis, characterized by acute cardiac dysfunction and high mortality, yet no specific therapy is currently available. Cordycepin (COR), a natural bioactive compound, has been reported to exert anti-inflammatory and cardioprotective effects; however, its role and underlying mechanisms in SICM remain unclear.</div></div><div><h3>Methods</h3><div>SICM was established in mice by intraperitoneal lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP). In vitro, HL-1 cells were treated with cytokine mixtures. COR was administered as a pre-treatment in both models. Cardiac function and myocardial injury were evaluated by echocardiography, histopathology, and biochemical assays. Transcriptome sequencing was performed to identify potential pathways, followed by validation using Western blotting and immunofluorescence. Mitochondrial function and cell death were assessed using CCK-8, flow cytometry, JC-1 staining, MitoTracker labeling, and transmission electron microscopy.</div></div><div><h3>Results</h3><div>COR markedly attenuated myocardial injury induced by LPS, CLP, and cytokine stimulation. Compared with the model group, COR improved cardiac function, increased 7-day survival, and reduced myocardial inflammatory responses. Transcriptomic profiling implicated PI3K/Akt/mTOR signaling, and subsequent in vivo and in vitro experiments supported pathway activation by COR. Mechanistically, COR restored mitochondrial homeostasis and alleviated oxidative stress, evidenced by decreased ROS and MDA and increased SOD activity, while enhancing mitochondrial membrane potential and ATP production. COR also suppressed cardiomyocyte apoptosis, reflected by reduced Bax expression and decreased ratios of Cleaved Caspase-3/Caspase-3 and Cleaved Caspase-9/Caspase-9, along with increased Bcl-2 expression.</div></div><div><h3>Conclusion</h3><div>COR mitigates inflammation, oxidative stress, and cardiomyocyte apoptosis in SICM via modulation of the PI3K/Akt/mTOR pathway, thereby attenuating myocardial injury and improving cardiac function. Collectively, these findings indicate that COR may serve as a potential novel therapeutic agent for the management of SICM.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112354"},"PeriodicalIF":3.7,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910563","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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