Pub Date : 2026-05-01Epub Date: 2026-01-19DOI: 10.1016/j.cellsig.2026.112384
Wenyu Zang , Wenshuai Zhu , Fubo Jing , He Qi , Xiaoli Ma , Yunshan Wang , Yanfei Jia
The Hh signaling pathway critically drives tumorigenesis and progression in multiple cancers, including gastrointestinal cancers such as gastric, hepatic, pancreatic, esophageal, and colorectal cancer. Aberrant Hh signaling pathway activation, often driven by ligands such as Sonic Hedgehog (Shh) and transcription factors such as Gli1/2, promotes tumor cell proliferation, survival, metastasis, cancer stem cells, and chemoresistance while inhibiting programmed cell death pathways. High levels of Hh signaling pathway activity are a characteristic feature of gastrointestinal cancers. Therapeutic targeting of the Hh signaling pathway has shown promise, with Smoothened (Smo) inhibitors approved for basal cell carcinoma but yielding mixed results in gastrointestinal cancer trials. Emerging strategies, including Hh inhibitors; natural compounds from traditional Chinese medicine; and combinations of chemotherapy, immunotherapy or radiation to induce cell death and remodel the tumor microenvironment, could lead to a new therapeutic avenue for gastrointestinal cancers. In this review, we summarize advances in our understanding of Hh-mediated cell death in gastrointestinal cancers and the role and mechanisms, and highlight the underlying therapeutic opportunities. These new findings advance the rapidly expanding field of translational cancer research focused on the Hh signaling pathway.
{"title":"The role of the hedgehog signaling pathway in the regulation of gastrointestinal cancer cell death","authors":"Wenyu Zang , Wenshuai Zhu , Fubo Jing , He Qi , Xiaoli Ma , Yunshan Wang , Yanfei Jia","doi":"10.1016/j.cellsig.2026.112384","DOIUrl":"10.1016/j.cellsig.2026.112384","url":null,"abstract":"<div><div>The Hh signaling pathway critically drives tumorigenesis and progression in multiple cancers, including gastrointestinal cancers such as gastric, hepatic, pancreatic, esophageal, and colorectal cancer. Aberrant Hh signaling pathway activation, often driven by ligands such as Sonic Hedgehog (Shh) and transcription factors such as Gli1/2, promotes tumor cell proliferation, survival, metastasis, cancer stem cells, and chemoresistance while inhibiting programmed cell death pathways. High levels of Hh signaling pathway activity are a characteristic feature of gastrointestinal cancers. Therapeutic targeting of the Hh signaling pathway has shown promise, with Smoothened (Smo) inhibitors approved for basal cell carcinoma but yielding mixed results in gastrointestinal cancer trials. Emerging strategies, including Hh inhibitors; natural compounds from traditional Chinese medicine; and combinations of chemotherapy, immunotherapy or radiation to induce cell death and remodel the tumor microenvironment, could lead to a new therapeutic avenue for gastrointestinal cancers. In this review, we summarize advances in our understanding of Hh-mediated cell death in gastrointestinal cancers and the role and mechanisms, and highlight the underlying therapeutic opportunities. These new findings advance the rapidly expanding field of translational cancer research focused on the Hh signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112384"},"PeriodicalIF":3.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017420","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 : 2026-04-01Epub Date: 2026-01-10DOI: 10.1016/j.cellsig.2026.112363
Meimei Jiang , Mingyi Zhao , Yeying Liu , Jing Liu , Nannan Liu , Jiehan Li , Wunan Mi , Guiyun Jia , Yang Fu , Lingling Zhang , Yingjie Zhang , Feng Wang
As Bcl-2 family members, PUMA and Bcl-XL played critical roles in mitochondrial apoptosis. However, whether they can regulate autophagy, especially mitophagy, is not understood at all. In this study, we explore the interaction among PUMA and Bcl-XL in different subcellular localizations, and their functions in autophagy and mitophagy respectively. The detailed mechanisms were determined by mitochondria purification, Co-IP, and western blot analysis. Moreover, living cell imaging was performed to determine the occurrence of mitophagy. We found that PUMA inhibited autophagy by interacting with Ulk1 and Beclin1 in the cytoplasm. Six mutants of PUMA were constructed to further study which part is responsible for the interaction, and the BH3 domain shows indispensability. When PUMA moved to mitochondria and formed a complex with Ulk1 and Bcl-XL, which played opposite roles, in promoting mitophagy. During this process, Ser96 of PUMA was indispensable for activating mitophagy. Besides, over-expressed PUMA or Bcl-XL promotes obvious mitophagy, and the real-time detection of lysosome and mitochondria shows fusion. Our results identified new functions and molecular mechanisms of PUMA and Bcl-XL in autophagy and mitophagy, which supplied theoretical bases for CRC therapy and other diseases.
{"title":"Dual-faced PUMA in CRC: A cytoplasmic autophagy repressor and mitochondrial mitophagy promoter","authors":"Meimei Jiang , Mingyi Zhao , Yeying Liu , Jing Liu , Nannan Liu , Jiehan Li , Wunan Mi , Guiyun Jia , Yang Fu , Lingling Zhang , Yingjie Zhang , Feng Wang","doi":"10.1016/j.cellsig.2026.112363","DOIUrl":"10.1016/j.cellsig.2026.112363","url":null,"abstract":"<div><div>As Bcl-2 family members, PUMA and Bcl-X<sub>L</sub> played critical roles in mitochondrial apoptosis. However, whether they can regulate autophagy, especially mitophagy, is not understood at all. In this study, we explore the interaction among PUMA and Bcl-X<sub>L</sub> in different subcellular localizations, and their functions in autophagy and mitophagy respectively. The detailed mechanisms were determined by mitochondria purification, Co-IP, and western blot analysis. Moreover, living cell imaging was performed to determine the occurrence of mitophagy. We found that PUMA inhibited autophagy by interacting with Ulk1 and Beclin1 in the cytoplasm. Six mutants of PUMA were constructed to further study which part is responsible for the interaction, and the BH3 domain shows indispensability. When PUMA moved to mitochondria and formed a complex with Ulk1 and Bcl-X<sub>L</sub>, which played opposite roles, in promoting mitophagy. During this process, Ser96 of PUMA was indispensable for activating mitophagy. Besides, over-expressed PUMA or Bcl-X<sub>L</sub> promotes obvious mitophagy, and the real-time detection of lysosome and mitochondria shows fusion. Our results identified new functions and molecular mechanisms of PUMA and Bcl-X<sub>L</sub> in autophagy and mitophagy, which supplied theoretical bases for CRC therapy and other diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112363"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958931","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 : 2026-04-01Epub Date: 2025-12-31DOI: 10.1016/j.cellsig.2025.112349
Xiaofei Duan , Zhipin Yan , Jie Gao , Zhihui Wang , Bowen Hu , An Zhao , Lei Liu , Minghao Li , Jihua Shi , Wenzhi Guo , Shuijun Zhang
Thioredoxin-related transmembrane protein 1 (TMX1), a member of the thioredoxin-like family, upregulated in certain human malignancies and is implicated in tumorigenesis and progression. However, its biological functions in hepatocellular carcinoma (HCC) remain largely unexplored. Through bioinformatic analysis and validation with clinical samples, it was determined that TMX1 expression is elevated in HCC patients and is associated with poor survival outcomes. Knocking down TMX1 resulted in a marked reduction in cell proliferation both in vivo and in vitro, whereas overexpressing TMX1 increased cell proliferation. Mechanistically, TMX1 binds to Fatty Acid-Binding Protein 5 (FABP5), thereby competitively blocking the interaction between FABP5 and the E3 ubiquitin ligase neuronally expressed developmentally downregulated 4 (NEDD4), and preventing K48-associated ubiquitination degradation of FABP5, thereby enhances the inhibition of FABP5-mediated ferroptosis signaling pathways. Furthermore, in TMX1-overexpressing HuH-7 cells, FABP5 knockdown negated the effects of TMX1 overexpression, suggesting that FABP5 mediates TMX1's regulation of HCC cell proliferation. Consequently, this study elucidates the mechanisms by which TMX1 contributes to HCC development, suggesting that TMX1 may serve as a potential biomarker and therapeutic target in the context of HCC.
{"title":"TMX1 promotes the progression of hepatocellular carcinoma by inhibiting ferroptosis via stabilizing FABP5","authors":"Xiaofei Duan , Zhipin Yan , Jie Gao , Zhihui Wang , Bowen Hu , An Zhao , Lei Liu , Minghao Li , Jihua Shi , Wenzhi Guo , Shuijun Zhang","doi":"10.1016/j.cellsig.2025.112349","DOIUrl":"10.1016/j.cellsig.2025.112349","url":null,"abstract":"<div><div>Thioredoxin-related transmembrane protein 1 (TMX1), a member of the thioredoxin-like family, upregulated in certain human malignancies and is implicated in tumorigenesis and progression. However, its biological functions in hepatocellular carcinoma (HCC) remain largely unexplored. Through bioinformatic analysis and validation with clinical samples, it was determined that TMX1 expression is elevated in HCC patients and is associated with poor survival outcomes. Knocking down TMX1 resulted in a marked reduction in cell proliferation both in vivo and in vitro, whereas overexpressing TMX1 increased cell proliferation. Mechanistically, TMX1 binds to Fatty Acid-Binding Protein 5 (FABP5), thereby competitively blocking the interaction between FABP5 and the E3 ubiquitin ligase neuronally expressed developmentally downregulated 4 (NEDD4), and preventing K48-associated ubiquitination degradation of FABP5, thereby enhances the inhibition of FABP5-mediated ferroptosis signaling pathways. Furthermore, in TMX1-overexpressing HuH-7 cells, FABP5 knockdown negated the effects of TMX1 overexpression, suggesting that FABP5 mediates TMX1's regulation of HCC cell proliferation. Consequently, this study elucidates the mechanisms by which TMX1 contributes to HCC development, suggesting that TMX1 may serve as a potential biomarker and therapeutic target in the context of HCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112349"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892206","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}
Activation of microglia triggers neuroinflammation, which subsequently leads to neurological dysfunction, representing a significant pathological mechanism underlying obesity-related cognitive impairment. Microglial lipophagy plays a critical role in regulating lipid homeostasis and inflammation; however, its involvement in obesity-related cognitive impairment remains largely unexplored. The accumulation of lipid droplets in microglia is a prominent feature of aging and reflects an imbalance in microglial lipid metabolism. CTRP9 is an important regulator in this process. The aim of this study was to investigate the potential role of CTRP9 in high-fat diet-induced disruption of microglial lipid metabolism. First, cognitive impairment was observed in an obesity model induced by a high-fat diet. We then observed a significant increase in lipid droplets in hippocampal microglia, inhibition of autophagic activity, and decreased CTRP9 expression in obese mice with cognitive impairment. Additionally, both BV2 and HMC3 cells stimulated with palmitic acid (PA) displayed lipid droplet accumulation, along with impaired lipophagy. Mechanistically, PA stimulation significantly reduced CTRP9 expression. To further investigate the role of CTRP9, we demonstrated that silencing CTRP9 exacerbated lipophagy impairment and increased lipid droplet accumulation in microglia. Conversely, overexpression of CTRP9 was able to reverse the aberrant activation of the PI3K/AKT/FOXO1 signaling pathway in PA-stimulated BV2 cells, thereby ameliorating these phenotypes. Taken together, these results suggest that CTRP9 plays a crucial regulatory role in lipid metabolism disorders in high-fat-stimulated microglia, and its mechanism may be closely linked to the dysfunction of the PI3K/AKT/FOXO1 signaling pathway.
{"title":"Role of CTRP9 in obesity-associated microglial dysregulation: Promoting lipophagy via the PI3K/AKT/FOXO1 signaling pathway","authors":"Peng-Quan Chen , Ya-Dong Wei , Xin Zheng , Quan-Tong Xu , Song-Lin Xu , Shuai He , Meng-Jie Xu , Jin-Fang Ge","doi":"10.1016/j.cellsig.2026.112358","DOIUrl":"10.1016/j.cellsig.2026.112358","url":null,"abstract":"<div><div>Activation of microglia triggers neuroinflammation, which subsequently leads to neurological dysfunction, representing a significant pathological mechanism underlying obesity-related cognitive impairment. Microglial lipophagy plays a critical role in regulating lipid homeostasis and inflammation; however, its involvement in obesity-related cognitive impairment remains largely unexplored. The accumulation of lipid droplets in microglia is a prominent feature of aging and reflects an imbalance in microglial lipid metabolism. CTRP9 is an important regulator in this process. The aim of this study was to investigate the potential role of CTRP9 in high-fat diet-induced disruption of microglial lipid metabolism. First, cognitive impairment was observed in an obesity model induced by a high-fat diet. We then observed a significant increase in lipid droplets in hippocampal microglia, inhibition of autophagic activity, and decreased CTRP9 expression in obese mice with cognitive impairment. Additionally, both BV2 and HMC3 cells stimulated with palmitic acid (PA) displayed lipid droplet accumulation, along with impaired lipophagy. Mechanistically, PA stimulation significantly reduced CTRP9 expression. To further investigate the role of CTRP9, we demonstrated that silencing CTRP9 exacerbated lipophagy impairment and increased lipid droplet accumulation in microglia. Conversely, overexpression of CTRP9 was able to reverse the aberrant activation of the PI3K/AKT/FOXO1 signaling pathway in PA-stimulated BV2 cells, thereby ameliorating these phenotypes. Taken together, these results suggest that CTRP9 plays a crucial regulatory role in lipid metabolism disorders in high-fat-stimulated microglia, and its mechanism may be closely linked to the dysfunction of the PI3K/AKT/FOXO1 signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112358"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958949","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 : 2026-04-01Epub 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":"2026-04-01","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 : 2026-04-01Epub 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":"2026-04-01","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 : 2026-04-01Epub Date: 2026-01-10DOI: 10.1016/j.cellsig.2026.112361
Tao Yang , Qianqian Jiang , Defei Tan , Hongfeng Yang , Yijun Shi , Junlan Zhou , Ying Li , Chenyang Liu , Lingling Li , Xin Yao , Qin Chen , Ying Zhou , Longfeng Jiang
Background
Notch signaling regulate innate immune cell function during tissue injury, while thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome activation drives lung inflammation. However, the role of Jagged1-mediated macrophage Notch1 signaling in regulating TXNIP/NLRP3 inflammasome function in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear.
Methods
To investigate this, we utilized wild-type (WT), floxed Notch1 (Notch1FL/FL) and myeloid-specific Notch1 knockout (Notch1M−KO) mice were intratracheal instill LPS (5 mg/kg) to induce ALI. In some Notch1M−KO mice, endogenous macrophage Foxo1 was knocked down using a Foxo1 siRNA mix combined with mannose-conjugated polymers before the LPS challenge. Primary AEC IIs from WT mice were transfected with CRISPR/Cas9-mediated Jagged1 knockout (KO) or Jagged1 activation (ACT) vector, challenged with LPS (100 ng/mL), and cocultured with bone marrow-derived macrophages (BMMs). BMMs from Notch1M−KO mice were also obtained and transfected with CRISPR/Cas9-mediated Foxo1 knockout (KO) vector before subjected to LPS challenged.
Results
Herein, we discovered that recombinant Jagged1 administration in WT mice reduces LPS-induced ALI by promoting Notch signaling activation. Apoptotic AEC IIs release Jagged1, which activates Notch1 signaling in macrophages. Notably, myeloid-specific Notch1 deficiency exacerbates LPS-induced inflammation response and oxidative stress, accompanied by elevated Foxo1 and dysregulated TXNIP/NLRP3 activity. Mechanistically, Notch intracellular domain (NICD) and Foxo1 colocalized in the nucleus, where Foxo1 competed with NICD for RBP-Jκ binding, impairing Notch1 signaling and promoting inflammasome activation. Importantly, Foxo1 deletion in macrophages rescued these effects.
Conclusions
Collectively, we characterized a novel molecular mechanism involving the Jagged1-Notch1-Foxo1 axis in regulating the TXNIP/NLRP3 pathway, which is dysregulated in ALI. These findings highlight the potential of targeting this pathway for therapeutic intervention in ALI.
{"title":"Jagged1-Notch1/Foxo1 signaling crosstalk regulates TXNIP/NLRP3 inflammasome to alleviate lung inflammation","authors":"Tao Yang , Qianqian Jiang , Defei Tan , Hongfeng Yang , Yijun Shi , Junlan Zhou , Ying Li , Chenyang Liu , Lingling Li , Xin Yao , Qin Chen , Ying Zhou , Longfeng Jiang","doi":"10.1016/j.cellsig.2026.112361","DOIUrl":"10.1016/j.cellsig.2026.112361","url":null,"abstract":"<div><h3>Background</h3><div>Notch signaling regulate innate immune cell function during tissue injury, while thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome activation drives lung inflammation. However, the role of Jagged1-mediated macrophage Notch1 signaling in regulating TXNIP/NLRP3 inflammasome function in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear.</div></div><div><h3>Methods</h3><div>To investigate this, we utilized wild-type (WT), floxed Notch1 (Notch1<sup>FL/FL</sup>) and myeloid-specific Notch1 knockout (Notch1<sup>M−KO</sup>) mice were intratracheal instill LPS (5 mg/kg) to induce ALI. In some Notch1<sup>M−KO</sup> mice, endogenous macrophage Foxo1 was knocked down using a Foxo1 siRNA mix combined with mannose-conjugated polymers before the LPS challenge. Primary AEC IIs from WT mice were transfected with CRISPR/Cas9-mediated Jagged1 knockout (KO) or Jagged1 activation (ACT) vector, challenged with LPS (100 ng/mL), and cocultured with bone marrow-derived macrophages (BMMs). BMMs from Notch1<sup>M−KO</sup> mice were also obtained and transfected with CRISPR/Cas9-mediated Foxo1 knockout (KO) vector before subjected to LPS challenged.</div></div><div><h3>Results</h3><div>Herein, we discovered that recombinant Jagged1 administration in WT mice reduces LPS-induced ALI by promoting Notch signaling activation. Apoptotic AEC IIs release Jagged1, which activates Notch1 signaling in macrophages. Notably, myeloid-specific Notch1 deficiency exacerbates LPS-induced inflammation response and oxidative stress, accompanied by elevated Foxo1 and dysregulated TXNIP/NLRP3 activity. Mechanistically, Notch intracellular domain (NICD) and Foxo1 colocalized in the nucleus, where Foxo1 competed with NICD for RBP-Jκ binding, impairing Notch1 signaling and promoting inflammasome activation. Importantly, Foxo1 deletion in macrophages rescued these effects.</div></div><div><h3>Conclusions</h3><div>Collectively, we characterized a novel molecular mechanism involving the Jagged1-Notch1-Foxo1 axis in regulating the TXNIP/NLRP3 pathway, which is dysregulated in ALI. These findings highlight the potential of targeting this pathway for therapeutic intervention in ALI.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112361"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958996","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 : 2026-04-01Epub 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":"2026-04-01","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 : 2026-04-01Epub Date: 2026-01-12DOI: 10.1016/j.cellsig.2026.112365
Fei Zhou , Yuanduo Li , Xiaotong Liang , Xiaoru Xie , Wenzhang Zheng , Zikai Chen , Xianghui Zou , Zhicong Liu , Feng Pan , Hui Zhu , Yuzhong Zheng
Chronic inflammation promotes esophageal cancer (EC) progression through NFκB activation, yet the downstream effector genes driving EC progression remain incompletely characterized. Here, we identify syndecan-4 (SDC4) as a new NFκB target gene that is upregulated in EC and associated with poor prognosis. The pro-inflammatory cytokine IL1β stimulates EC cell proliferation and concurrently induces SDC4 expression in an NFκB-dependent manner. Mechanistically, NFκB directly binds to the SDC4 promoter region, which is enriched with the active chromatin marker H3K27Ac. Functional studies demonstrate that SDC4 is necessary for IL1β-driven proliferation, as its knockdown suppresses, whereas overexpression enhances EC cell proliferation. Notably, the natural compound epigallocatechin gallate (EGCG) effectively blocks this IL1β-NFκB-SDC4 axis by inhibiting NFκB nuclear translocation, thereby attenuating SDC4 upregulation and subsequent EC cell proliferation. Our findings establish SDC4 as a critical molecular link between inflammation and EC progression, and highlight EGCG as a potential therapeutic candidate targeting this pathway.
{"title":"The IL1β-NFκB-SDC4 signaling Axis promotes esophageal cancer cell proliferation and is suppressed by EGCG","authors":"Fei Zhou , Yuanduo Li , Xiaotong Liang , Xiaoru Xie , Wenzhang Zheng , Zikai Chen , Xianghui Zou , Zhicong Liu , Feng Pan , Hui Zhu , Yuzhong Zheng","doi":"10.1016/j.cellsig.2026.112365","DOIUrl":"10.1016/j.cellsig.2026.112365","url":null,"abstract":"<div><div>Chronic inflammation promotes esophageal cancer (EC) progression through NFκB activation, yet the downstream effector genes driving EC progression remain incompletely characterized. Here, we identify syndecan-4 (SDC4) as a new NFκB target gene that is upregulated in EC and associated with poor prognosis. The pro-inflammatory cytokine IL1β stimulates EC cell proliferation and concurrently induces SDC4 expression in an NFκB-dependent manner. Mechanistically, NFκB directly binds to the SDC4 promoter region, which is enriched with the active chromatin marker H3K27Ac. Functional studies demonstrate that SDC4 is necessary for IL1β-driven proliferation, as its knockdown suppresses, whereas overexpression enhances EC cell proliferation. Notably, the natural compound epigallocatechin gallate (EGCG) effectively blocks this IL1β-NFκB-SDC4 axis by inhibiting NFκB nuclear translocation, thereby attenuating SDC4 upregulation and subsequent EC cell proliferation. Our findings establish SDC4 as a critical molecular link between inflammation and EC progression, and highlight EGCG as a potential therapeutic candidate targeting this pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112365"},"PeriodicalIF":3.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975648","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 : 2026-04-01Epub 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":"2026-04-01","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号