Pub 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":"2026-01-19","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 : 2026-01-17DOI: 10.1016/j.cellsig.2026.112369
Tao Ran , Qing-xiu Zhang , Hua-yue Wu , Shu Feng , Lu Han , Yuan Qin , Guo-yuan Lin , Ya Zhang , Shi-liang Li , Ji-yu Chen , Yu-mei Zhou , Shi-qian Cai , Xue-ke Zhao
Liver fibrosis (LF) represents a common wound-healing response to various forms of liver injury. Activation of hepatic stellate cells (HSCs) is a central event in this process. Aerobic glycolysis plays a critical role in the sustained activation of HSCs. Human aldo-keto reductase family 1 member C3 (AKR1C3), a multifunctional enzyme, is upregulated in many diseases and has been identified as a drug target in cancer treatment. However, the underlying mechanism through which AKR1C3 is involved in LF remains unclear. This study indicated the elevated expression of AKR1C3 in the fibrotic tissues of both humans and rats. AKR1C3 overexpression stimulated the proliferation, migration, and activation of HSCs in vitro. These effects were reversed by inhibiting AKR1C3. Based on RNA-seq analysis, we investigated the underlying mechanism of AKR1C3 and found that glycolysis and the AKT/mTOR pathway may contribute to the effect of AKR1C3 on LF. Mechanistically, AKR1C3 may act as a molecular scaffold to mediate the binding of mTORC2 to AKT, thereby promoting the phosphorylation of AKT at Ser473 and activating the signaling pathway. In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the AKT/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and AKT inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies.
{"title":"AKR1C3 promotes aerobic glycolysis in hepatic stellate cells via the AKT/mTOR pathway to induce liver fibrosis","authors":"Tao Ran , Qing-xiu Zhang , Hua-yue Wu , Shu Feng , Lu Han , Yuan Qin , Guo-yuan Lin , Ya Zhang , Shi-liang Li , Ji-yu Chen , Yu-mei Zhou , Shi-qian Cai , Xue-ke Zhao","doi":"10.1016/j.cellsig.2026.112369","DOIUrl":"10.1016/j.cellsig.2026.112369","url":null,"abstract":"<div><div>Liver fibrosis (LF) represents a common wound-healing response to various forms of liver injury. Activation of hepatic stellate cells (HSCs) is a central event in this process. Aerobic glycolysis plays a critical role in the sustained activation of HSCs. Human aldo-keto reductase family 1 member C3 (AKR1C3), a multifunctional enzyme, is upregulated in many diseases and has been identified as a drug target in cancer treatment. However, the underlying mechanism through which AKR1C3 is involved in LF remains unclear. This study indicated the elevated expression of AKR1C3 in the fibrotic tissues of both humans and rats. AKR1C3 overexpression stimulated the proliferation, migration, and activation of HSCs in vitro. These effects were reversed by inhibiting AKR1C3. Based on RNA-seq analysis, we investigated the underlying mechanism of AKR1C3 and found that glycolysis and the AKT/mTOR pathway may contribute to the effect of AKR1C3 on LF. Mechanistically, AKR1C3 may act as a molecular scaffold to mediate the binding of mTORC2 to AKT, thereby promoting the phosphorylation of AKT at Ser473 and activating the signaling pathway. In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the AKT/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and AKT inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112369"},"PeriodicalIF":3.7,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003187","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 : 2026-01-16DOI: 10.1016/j.cellsig.2026.112367
Gustavo A. Sosa, Betsy Crosswhite, Austin N. Kirschner
{"title":"Cellular signaling and radioresistance in prostate cancer","authors":"Gustavo A. Sosa, Betsy Crosswhite, Austin N. Kirschner","doi":"10.1016/j.cellsig.2026.112367","DOIUrl":"10.1016/j.cellsig.2026.112367","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112367"},"PeriodicalIF":3.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997430","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 : 2026-01-12DOI: 10.1016/j.cellsig.2026.112366
Junfeng Li , Zibing Qian , Zheyu Li , Xiaorong Mao , Aipin Tian , Xuebin Peng , Zhongxia Yang , Kai Yang
Background & aim
M2 macrophages are key drivers of immune-mediated liver injury. The aim of this study was to investigate the mechanisms by which Annexin A5 regulates ferroptosis in M2 macrophages and its protective effect against immune liver injury.
Methods
The colocalization of ferroptosis in M2 macrophages from autoimmune hepatitis (AIH) patients and mice with ConA-induced immune liver injury was analyzed via laser confocal microscopy. The effects of ferritinophagy and autophagosomal–lysosomal fusion on the regulation of ferroptosis in M2 macrophages by Annexin A5 were investigated through mCherryGFP–LC3B adenovirus transfection. Ferroptosis of M2 macrophages was studied by using si-RNA and chemical inhibitors and agonist of nuclear factor erythroid 2-related factor 2 (NRF2) and extracellular signal-regulated kinase (ERK). Bone marrow-derived macrophages were polarized into M2 macrophages for use in cell transfer experiments. A coculture model of M2 macrophages and hepatocytes was established to study the effect of M2 macrophages on liver regeneration.
Results
M2 macrophages are highly sensitive to ferroptosis in immune-mediated liver injury, and Annexin A5 can effectively inhibit ferroptosis in M2 macrophages, thereby exerting a protective effect on immune-mediated liver injury. Annexin A5 alleviates ferritinophagy by inhibiting the degradation of NRF2 and the phosphorylation of ERK1/2, as well as by inhibiting autophagosome–lysosome fusion. This enhances the resistance of M2 macrophages to ferroptosis and improves outcomes in immune-related liver injury. Additionally, the inhibition of ferroptosis in M2 macrophages promotes hepatocyte regeneration.
Conclusion
Our findings comprehensively reveal that the modulation of the NRF2-ERK1/2 signaling pathway by Annexin A5 is essential for mitigating ferroptosis in M2 macrophages during immune-mediated liver injury. Therefore, targeting Annexin A5 may offer novel therapeutic approaches for the treatment of immune-mediated liver injury.
{"title":"Annexin A5 ameliorates immune-mediated liver injury by regulating ferritinophagy–ferroptosis in M2 macrophages via the NRF2/ERK pathway","authors":"Junfeng Li , Zibing Qian , Zheyu Li , Xiaorong Mao , Aipin Tian , Xuebin Peng , Zhongxia Yang , Kai Yang","doi":"10.1016/j.cellsig.2026.112366","DOIUrl":"10.1016/j.cellsig.2026.112366","url":null,"abstract":"<div><h3>Background & aim</h3><div>M2 macrophages are key drivers of immune-mediated liver injury. The aim of this study was to investigate the mechanisms by which Annexin A5 regulates ferroptosis in M2 macrophages and its protective effect against immune liver injury.</div></div><div><h3>Methods</h3><div>The colocalization of ferroptosis in M2 macrophages from autoimmune hepatitis (AIH) patients and mice with ConA-induced immune liver injury was analyzed via laser confocal microscopy. The effects of ferritinophagy and autophagosomal–lysosomal fusion on the regulation of ferroptosis in M2 macrophages by Annexin A5 were investigated through mCherryGFP–LC3B adenovirus transfection. Ferroptosis of M2 macrophages was studied by using si-RNA and chemical inhibitors and agonist of nuclear factor erythroid 2-related factor 2 (NRF2) and extracellular signal-regulated kinase (ERK). Bone marrow-derived macrophages were polarized into M2 macrophages for use in cell transfer experiments. A coculture model of M2 macrophages and hepatocytes was established to study the effect of M2 macrophages on liver regeneration.</div></div><div><h3>Results</h3><div>M2 macrophages are highly sensitive to ferroptosis in immune-mediated liver injury, and Annexin A5 can effectively inhibit ferroptosis in M2 macrophages, thereby exerting a protective effect on immune-mediated liver injury. Annexin A5 alleviates ferritinophagy by inhibiting the degradation of NRF2 and the phosphorylation of ERK1/2, as well as by inhibiting autophagosome–lysosome fusion. This enhances the resistance of M2 macrophages to ferroptosis and improves outcomes in immune-related liver injury. Additionally, the inhibition of ferroptosis in M2 macrophages promotes hepatocyte regeneration.</div></div><div><h3>Conclusion</h3><div>Our findings comprehensively reveal that the modulation of the NRF2-ERK1/2 signaling pathway by Annexin A5 is essential for mitigating ferroptosis in M2 macrophages during immune-mediated liver injury. Therefore, targeting Annexin A5 may offer novel therapeutic approaches for the treatment of immune-mediated liver injury.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112366"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984352","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 : 2026-01-12DOI: 10.1016/j.cellsig.2026.112368
Marwah M. Al-Mathkour , Abdulrahman M. Dwead , Kezhan Khazaw , Bekir Cinar
The transcriptional coregulator YAP1 and the receptor tyrosine kinase EPHA3 regulate key cellular processes, including cell interactions, motility, survival, tissue development, carcinogenesis, and metastasis. Although their individual roles have been extensively studied, their cooperative functions remain poorly understood. Here, we investigated the relationship between EPHA3 and YAP1 in human prostate tumor tissues and cell models. Integrated transcriptomic and immunological analyses reveal a strong positive correlation between YAP1 and EPHA3 expression, which is significantly associated with tumor progression. EPHA3 knockout reduces cell proliferation and increases sensitivity to the androgen receptor inhibitor enzalutamide and the YAP1-TEAD inhibitor CA3 in vitro. EPHA3 depletion also reduces GTP-bound active RHOA and phosphorylated ERK levels and differentially affects epithelial-mesenchymal transition and cancer stem cell programs. In addition, EPHA3 silencing attenuates cell migration and invasion, an effect dependent on YAP1 activation. Bioinformatics analysis further indicates that high YAP1 and EPHA3 correlate with developmental and EMT-related gene signatures. These results demonstrate that the YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression, and may serve as a promising cancer drug target.
{"title":"The YAP1 and EPHA3 receptor tyrosine kinase axis regulates cellular plasticity and treatment response","authors":"Marwah M. Al-Mathkour , Abdulrahman M. Dwead , Kezhan Khazaw , Bekir Cinar","doi":"10.1016/j.cellsig.2026.112368","DOIUrl":"10.1016/j.cellsig.2026.112368","url":null,"abstract":"<div><div>The transcriptional coregulator YAP1 and the receptor tyrosine kinase EPHA3 regulate key cellular processes, including cell interactions, motility, survival, tissue development, carcinogenesis, and metastasis. Although their individual roles have been extensively studied, their cooperative functions remain poorly understood. Here, we investigated the relationship between EPHA3 and YAP1 in human prostate tumor tissues and cell models. Integrated transcriptomic and immunological analyses reveal a strong positive correlation between YAP1 and EPHA3 expression, which is significantly associated with tumor progression. EPHA3 knockout reduces cell proliferation and increases sensitivity to the androgen receptor inhibitor enzalutamide and the YAP1-TEAD inhibitor CA3 in vitro. EPHA3 depletion also reduces GTP-bound active RHOA and phosphorylated ERK levels and differentially affects epithelial-mesenchymal transition and cancer stem cell programs. In addition, EPHA3 silencing attenuates cell migration and invasion, an effect dependent on YAP1 activation. Bioinformatics analysis further indicates that high YAP1 and EPHA3 correlate with developmental and EMT-related gene signatures. These results demonstrate that the YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression, and may serve as a promising cancer drug target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112368"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984478","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 : 2026-01-12DOI: 10.1016/j.cellsig.2026.112364
Xue Yang , Yuanru Wang , Luyao Li , Qiqi Lei , Liuyan Xiang , Xiaoqian Zhang , Jie Liu , Yajun Cao , Huifang Li , Xuejun Li
Background
Pulmonary fibrosis, a well-known chronic and progressive lung disease, primarily impacts the interstitial tissues of the lungs, with a lack of effective therapies. Nobiletin is a polymethoxyflavonoid that exhibits characteristics of BH3 mimetics. It is mainly extracted from citrus peels and is known for its diverse pharmacological activities. Given the unsatisfactory clinical trial results of nintedanib, a combined treatment approach may represent a viable strategy for combating pulmonary fibrosis.
Methods
An in vitro pulmonary fibrosis model was established by inducing MRC-5 cells with transforming growth factor-β1 (TGF-β1). The impact of nobiletin combined with nintedanib on the migration of MRC-5 cells was assessed by wound healing and Transwell assays. Immunofluorescence and Western blot analyses were employed to assess the effect of drug combination on fibrosis-related markers, while Co-Immunoprecipitation (Co-IP) experiments were performed to assess the effects on autophagy. The anti-fibrotic effects and potential mechanisms of the combination of nobiletin and nintedanib were further explored using a bleomycin-induced pulmonary fibrosis model in C57BL/6 J mice.
Results
In vitro, the combination of nobiletin and nintedanib significantly inhibited MRC-5 cells' migration and extracellular matrix deposition, while simultaneously promoting apoptosis and autophagy. In addition, this combination exerted an anti-pulmonary fibrosis effect by regulating epigenetic mechanisms and the PI3K-AKT-mTOR signaling pathway. In vivo studies further revealed that the combination of nobiletin and nintedanib significantly reduced hydroxyproline levels in mice, attenuated lung inflammation, and helped to limit or prevent collagen accumulation.
Conclusions
Our study demonstrates that the combination of nobiletin and nintedanib exhibits promising anti-fibrotic effects both in vitro and in vivo.
{"title":"Anti-fibrotic activity of nobiletin and nintedanib: In vitro and in vivo evidence in pulmonary fibrosis models","authors":"Xue Yang , Yuanru Wang , Luyao Li , Qiqi Lei , Liuyan Xiang , Xiaoqian Zhang , Jie Liu , Yajun Cao , Huifang Li , Xuejun Li","doi":"10.1016/j.cellsig.2026.112364","DOIUrl":"10.1016/j.cellsig.2026.112364","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary fibrosis, a well-known chronic and progressive lung disease, primarily impacts the interstitial tissues of the lungs, with a lack of effective therapies. Nobiletin is a polymethoxyflavonoid that exhibits characteristics of BH3 mimetics. It is mainly extracted from citrus peels and is known for its diverse pharmacological activities. Given the unsatisfactory clinical trial results of nintedanib, a combined treatment approach may represent a viable strategy for combating pulmonary fibrosis.</div></div><div><h3>Methods</h3><div>An <em>in vitro</em> pulmonary fibrosis model was established by inducing MRC-5 cells with transforming growth factor-β1 (TGF-β1). The impact of nobiletin combined with nintedanib on the migration of MRC-5 cells was assessed by wound healing and Transwell assays. Immunofluorescence and Western blot analyses were employed to assess the effect of drug combination on fibrosis-related markers, while Co-Immunoprecipitation (Co-IP) experiments were performed to assess the effects on autophagy. The anti-fibrotic effects and potential mechanisms of the combination of nobiletin and nintedanib were further explored using a bleomycin-induced pulmonary fibrosis model in C57BL/6 J mice.</div></div><div><h3>Results</h3><div><em>In vitro,</em> the combination of nobiletin and nintedanib significantly inhibited MRC-5 cells' migration and extracellular matrix deposition, while simultaneously promoting apoptosis and autophagy. In addition, this combination exerted an anti-pulmonary fibrosis effect by regulating epigenetic mechanisms and the PI3K-AKT-mTOR signaling pathway. <em>In vivo</em> studies further revealed that the combination of nobiletin and nintedanib significantly reduced hydroxyproline levels in mice, attenuated lung inflammation, and helped to limit or prevent collagen accumulation.</div></div><div><h3>Conclusions</h3><div>Our study demonstrates that the combination of nobiletin and nintedanib exhibits promising anti-fibrotic effects both <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112364"},"PeriodicalIF":3.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984500","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 : 2026-01-12DOI: 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":"2026-01-12","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 : 2026-01-10DOI: 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":"2026-01-10","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}
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":"2026-01-10","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 : 2026-01-10DOI: 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":"2026-01-10","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}
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