Cellular signalling最新文献

{"title":"Rigosertib promotes ferroptosis in colorectal cancer by increasing Keap1, reducing Nrf2/SLC7A11 signaling, and facilitating autophagic GPX4 degradation.","authors":"Yongkang Shi, Qiliang Lu, Ziwei Wang, Shanen Jin, Yue Wu, Long Zhang, Jun Ma","doi":"10.1016/j.cellsig.2026.112995","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112995","url":null,"abstract":"<p><p>Colorectal cancer (CRC) ranks among the leading malignancies worldwide in both incidence and mortality, and its treatment continues to face major challenges such as chemoresistance and tumor metastasis. This study aims to investigate the potential therapeutic value and underlying mechanisms of the multikinase inhibitor Rigosertib (Rig) in CRC. Our findings demonstrate that Rig markedly suppresses the proliferation, migration, and invasion of CRC cells while inducing apoptosis. Transcriptomic analyses suggest that ferroptosis may be involved in Rig's antitumor activity. Subsequent experiments confirm that Rig induces typical features of ferroptosis. Mechanistically, Rig exerts its effects through a dual regulatory mechanism. On one hand, it upregulates Keap1 expression, thereby suppressing the Nrf2/SLC7A11 signaling pathway and weakening the cellular antioxidant defense. On the other hand, Rig enhances autophagic flux, promoting the autophagy-lysosome-dependent degradation of GPX4, a key regulator of ferroptosis. Notably, both the Nrf2 pathway agonist KI696 and the autophagy inhibitor 3-methyladenine partially reverse Rig-induced ferroptosis, while GPX4 overexpression markedly attenuates Rig's cytotoxicity, confirming the crucial roles of these pathways in its mechanism of action. Moreover, Rig exhibits a pronounced synergistic antitumor effect with 5-fluorouracil in vitro. In xenograft mouse models, Rig treatment effectively suppresses tumor growth without causing significant systemic toxicity. This study, for the first time, reveals that Rig induces ferroptosis through dual mechanisms involving coordinated regulation of the Keap1/Nrf2/SLC7A11 axis and autophagy-dependent degradation of GPX4. These findings provide a novel theoretical foundation and a promising therapeutic strategy for colorectal cancer treatment.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112995"},"PeriodicalIF":4.7,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SSBP1 affects lung adenocarcinoma proliferation by regulating ferroptosis through the ERK/NRF2/GPX4 signaling pathway.","authors":"Fei Li, Jincheng Wu, Yangfan Zhou, Xiaolei Zhu, Yibin Li, Jingwei Chen, Kaiming Qiu, Weifeng Cai, Zhicai Lin, Guojun Geng, Yanjun Mi","doi":"10.1016/j.cellsig.2026.112970","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112970","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) accounts for roughly half of all lung cancer cases and novel therapeutic targets remain scarce. Ferroptosis, an iron-dependent form of regulated cell death, offers a promising strategy to combat therapy resistance. Mitochondrial single-stranded DNA-binding protein 1 (SSBP1) is critical for mitochondrial genome stability, but its role in ferroptosis and LUAD progression remains undefined.</p><p><strong>Methods: </strong>We analyzed SSBP1 expression and prognostic value in LUAD using public datasets and clinical specimens. In vitro, we used SSBP1 knockdown/overexpression in LUAD cell lines to assess cell viability, ferroptosis markers (Fe²⁺, Lipid ROS, MDA, rescue experiments), and mitochondrial function. Transcriptomic sequencing, GSEA, and Western blot were employed to identify the underlying pathway. The therapeutic potential of SSBP1 inhibition combined with the ferroptosis inducer RSL3 was validated in vitro and in a xenograft mouse model.</p><p><strong>Results: </strong>High SSBP1 expression is associated with patient prognosis and restrains lipid peroxidation by sustaining ERK-dependent NRF2 nuclear translocation and subsequent HO-1 and GPX4 expression. Loss of SSBP1 impairs this antioxidant signaling axis, leading to increased ferrous ions and lipid ROS within LUAD cells, ultimately sensitized LUAD cells to RSL3, significantly enhancing ferroptosis and inhibiting tumor growth in vivo. Furthermore, mitochondrial damage resulting from ferroptosis in cancer cells exacerbates the mitochondrial apoptosis pathway induced by SSBP1 dysregulation.</p><p><strong>Conclusion: </strong>SSBP1, a mitochondrial-localized protein associated with LUAD patient prognosis, promotes LUAD progression by inhibiting ferroptosis through the ERK/NRF2/GPX4 axis.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112970"},"PeriodicalIF":4.7,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcription factor Sp1 promotes malignant phenotypes in non-small cell lung cancer by regulating PHGDH.","authors":"Shan Liu, Fang Zhang, Xinhao Lu, Jiayang Huang, Jiamin Luo, Huan Xia, Yan Dou, Qi Zeng, Tiantian Yang, Chu I Ta, Hanrui Chen, Wei Guo","doi":"10.1016/j.cellsig.2026.112959","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112959","url":null,"abstract":"<p><p>Phosphoglycerate dehydrogenase (PHGDH) participates in serine biosynthesis and has been implicated in cancer metabolism. However, how PHGDH expression is controlled in non-small cell lung cancer (NSCLC) and whether this regulation is linked to tumor behavior remain unclear. We examined PHGDH expression in paired NSCLC and adjacent non-tumor (ANT) tissues and assessed its association with patient survival. In A549 and H1299 cells, PHGDH and Sp1 were manipulated to evaluate their effects on cell growth, migration, invasion, sphere formation, and metabolic parameters. Serine supplementation and PHGDH inhibitors were used to further examine PHGDH-associated sphere formation. The interaction between Sp1 and the PHGDH promoter was investigated using DNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays, and functional effects were further evaluated in xenograft models. PHGDH expression was higher in NSCLC tissues than in ANT tissues, and high PHGDH expression was associated with shorter overall survival. PHGDH modulation altered cell proliferation, migration, invasion, and sphere formation. PHGDH overexpression increased intracellular serine and glycine contents and relative NADPH levels and enhanced FCCP-stimulated OCR and oligomycin-stimulated ECAR. PHGDH knockdown produced the opposite changes and increased ROS levels. l-serine supplementation increased sphere formation after PHGDH knockdown, whereas NCT-503 and CBR-5884 attenuated the increase caused by PHGDH overexpression. Sp1 bound to the PHGDH promoter, and its expression was positively correlated with PHGDH in clinical specimens. Altering Sp1 expression resulted in parallel changes in PHGDH and the associated cellular phenotypes, whereas PHGDH knockdown weakened the effects of Sp1 overexpression both in vitro and in xenograft tumors. These findings indicate that PHGDH is transcriptionally regulated by Sp1 and contributes to tumor growth and stemness-related features in NSCLC.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112959"},"PeriodicalIF":4.7,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pannexin-1 (PANX1) in Metabolic Diseases: Structural Basis, Molecular Mechanisms, and Pharmacological Significance.","authors":"Guoqiang Fu, Zhujun Wang, Binfen Rao, Jie Liu, Hui Ouyang","doi":"10.1016/j.cellsig.2026.112993","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112993","url":null,"abstract":"<p><p>Metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), atherosclerosis (AS), and diabetes-related complications, are characterized by disrupted glucose and lipid metabolism, chronic inflammation, oxidative stress, and progressive tissue dysfunction. Pannexin-1 (PANX1), a large-pore membrane channel that mediates regulated ATP release, has emerged as an important interface between metabolic stress and extracellular purinergic signaling. PANX1 influences metabolic homeostasis through ATP-dependent and broader signaling mechanisms that regulate insulin action and secretion, hepatic glucose and lipid metabolism, autophagy, vascular function, inflammatory responses, and regulated cell death. Its effects are highly context dependent. PANX1 can support metabolic homeostasis in adipocytes, pancreatic β cells, hepatocytes, and selected vascular cell populations, whereas sustained or dysregulated PANX1 signaling may promote inflammation, vascular dysfunction, ferroptosis, and pyroptosis under metabolic stress. These divergent actions are shaped by cellular origin, disease stage, and the local metabolic environment. This review summarizes current understanding of PANX1 structure, channel gating, and regulatory mechanisms and integrates predominantly preclinical evidence for its involvement in metabolic homeostasis and related diseases. We further examine the interactions of PANX1 with purinergic signaling, inflammation, oxidative stress, organelle homeostasis, and regulated cell death, together with current pharmacological strategies targeting PANX1. Although most available PANX1 modulators remain primarily mechanistic tools and lack direct evidence of therapeutic efficacy in metabolic disease models, these findings provide a foundation for the future development and evaluation of more selective PANX1-targeted interventions.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112993"},"PeriodicalIF":4.7,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of USP38 in cellular stress adaptation: Context-dependent ubiquitin chain editing.","authors":"Zihan Wang, Wenbo Wang, Lin Wei, Haocheng Wang, Lina Yang","doi":"10.1016/j.cellsig.2026.112983","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112983","url":null,"abstract":"<p><p>Ubiquitin-specific protease 38 (USP38) edits ubiquitin chains on specific substrates, generating distinct biological outputs under different stress conditions, and thus functions as a context-dependent ubiquitin chain-editing enzyme. USP38 has recently been implicated in innate immunity, inflammatory transcription, fibrotic remodeling, hypoxic adaptation, lipid metabolism, genome maintenance, and tumor progression. However, available studies are scattered across distinct substrates and disease models, potentially leading to an oversimplified view of USP38 as merely a protein-stabilizing factor. Accordingly, this review integrates the molecular functions of USP38 from substrate and ubiquitin-chain-type-dependent perspectives and proposes that USP38 can be viewed as a context-dependent ubiquitin-chain modifier. By removing or remodeling specific ubiquitin chains, USP38 can alter substrate stability, regulate signaling duration, and reset the threshold of cellular stress responses. USP38 acts on diverse substrates, and distinct USP38- substrate axes can translate chain-type-specific deubiquitination into diverse biological outcomes, including inflammatory and fibrotic responses, hypoxic and metabolic adaptation, ferroptosis-associated vulnerabilities, DNA repair, and therapeutic responses, thereby establishing mechanistic links among these processes. Available evidence indicates that USP38-mediated deubiquitination is determined by the linkage type and modification site removed from a given substrate, with functional outcomes ranging from protein stabilization and altered enzymatic activity to subsequent substrate degradation. This review further integrates substrate engagement and complex recruitment, regulatory modifications of USP38, cell type, and stimulus-dependent interaction dynamics to explain how these molecular changes translate into distinct biological outcomes under diverse stress conditions. We also separate well-validated substrate mechanisms from integrative models that remain to be tested. Therefore, USP38-dependent stress-adaptation networks may create exploitable therapeutic vulnerabilities in specific tumors and chronic inflammatory diseases, although systemic inhibition of USP38 may also impair normal tissue homeostasis. Future studies should advance from validating single substrates to exploring chain typ -resolved ubiquitinomics, mapping stress-conditioned interactomes, and developing biomarker - guided, context-specific therapeutic strategies.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112983"},"PeriodicalIF":4.7,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An anti-invasion endogenous tRNA-derived small RNA (3'-tRF^AlaAGC) alleviates endometriosis by suppressing MCCC1 mediated EMT.","authors":"Hengmei Shi, Senhui Zhang, Huyang Hou, Tong Li, Danni He, Deshuo Jiang, Xin Cheng, Le Ma, Xuan Lin, Yangkaiyuan Liu, Zheng Ding, Hongjie Ruan, Ziyi Fu, Xiaoyan Shi","doi":"10.1016/j.cellsig.2026.112990","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112990","url":null,"abstract":"<p><p>Endometriosis is an invasive gynecological disorder, characterized by occult ectopic endometrial growth. Nascent endogenous tRNA-derived fragments occur across various disease, yet its pathology mechanistic pathways in endometriosis remain poorly defined. Downregulated 3'-tRF^AlaAGC validated from endometrial lesions and serum was demonstrated to suppress the invasion of endometriosis. Indeed, we identified that nuclear translocation of p65 mediated by MCCC1 protein was attenuated due to the occurrence of 3'-tRF^AlaAGC-MCCC1 compound relying on the 383-494aa of MCCC1, a unique binding site where 3'-tRF^AlaAGC directly bond to MCCC1. Hence, the activation of NF-κB pathway was inhibited, hindering the epithelial-mesenchymal transition related to the progression of endometriosis. Moreover, 3'-tRF^AlaAGC alleviated lesion burden in endometriosis mice, and the precious predictive efficiency in serum through the Machine learning. Understanding the 3'-tRF^AlaAGC provides a critical opportunity to dissect the mechanisms driving endometriosis progression, opening new avenues to diagnose and halt endometriosis in its tracks.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112990"},"PeriodicalIF":4.7,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enterochromaffin cell-derived 5-HT contributes to dexamethasone protection against cisplatin-induced nausea-related responses.","authors":"Dongping Lyu, Shichen Fu, Junyan Qu, Jinghui Zhang, Wenxin Zhang, Xia Wang, Lixiang Li, Yanqing Li, Xiuli Zuo","doi":"10.1016/j.cellsig.2026.112991","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112991","url":null,"abstract":"<p><p>Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a major peripheral mediator of cisplatin-induced nausea and emesis. Dexamethasone is a cornerstone of antiemetic prophylaxis, yet whether dexamethasone regulates small-intestinal enterochromaffin-cell 5-HT output during cisplatin challenge and thereby influences downstream gut-brain responses remains unknown. We investigated whether dexamethasone suppresses EC-derived 5-HT and whether this epithelial mechanism contributes to protection against cisplatin-induced nausea-related responses. Three complementary approaches were used: (i) human gastrointestinal single-cell data and biopsy specimens to assess glucocorticoid receptor expression; (ii) primary mouse small-intestinal organoids to examine basal, cisplatin-evoked, and interleukin-33-evoked 5-HT responses; and (iii) cisplatin-treated mice to evaluate conditioned flavor aversion, pica, food and water intake, body-weight change, and nucleus of the solitary tract c-Fos activation. Intestinal epithelial Tph1-deficient mice and the 5-HT precursor 5-hydroxytryptophan were used for functional validation. Glucocorticoid receptor was broadly expressed in gastrointestinal EC cells. In organoids, dexamethasone reduced Tph1 expression, TPH1 protein abundance, and extracellular 5-HT without decreasing EC-cell abundance, and suppressed cisplatin- and interleukin-33-evoked 5-HT responses. RU486 counteracted dexamethasone-induced reductions in Tph1 expression and extracellular 5-HT during cisplatin challenge. In vivo, dexamethasone attenuated cisplatin-induced intestinal Tph1 expression, tissue 5-HT, nausea-related behavioral responses, and brainstem c-Fos activation, whereas RU486 weakened these effects. Dexamethasone did not significantly improve the measured outcomes in intestinal epithelial Tph1-deficient mice, whereas 5-hydroxytryptophan counteracted its behavioral and brainstem effects in wild-type mice. Together, these findings support a contribution of intestinal EC-derived 5-HT to dexamethasone-associated protection against cisplatin-induced nausea-related responses in mice.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112991"},"PeriodicalIF":4.7,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Antitumor effects of isoliquiritin on oral squamous cell carcinoma by VEGFC/FLT4-PI3K/AKT signaling axis\" [Cell. Signal. 149 (2027) 112863].","authors":"Yiwen Qin, Han Wu, Yinyu Wang, Ziqiao Zhuang, Fengyuan Ma, Sihao Chen, Zhaorong Xiao, He Shi, Dongxu Wang, Weiwei Liu","doi":"10.1016/j.cellsig.2026.112971","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112971","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112971"},"PeriodicalIF":4.7,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149318484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"The role of IL-6 in tumor immunity and related research progress\" [Cell. Signal. 143 (2026) 112460].","authors":"Ping Huang, Rong Yin, Weina Xu, Shenggeng Wang, Hongmei Yong, Tian Yang","doi":"10.1016/j.cellsig.2026.112977","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112977","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112977"},"PeriodicalIF":4.7,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149318485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Histone H4K12 lactylation promotes malignancy progression in triple-negative breast cancer through SLFN5 downregulation\" [Cell. Signal. 124 (2024) 111468].","authors":"Jingyi Li, Ziyu Chen, Mingming Jin, Xuefeng Gu, Yuhan Wang, Gang Huang, Weiming Zhao, Changlian Lu","doi":"10.1016/j.cellsig.2026.112942","DOIUrl":"https://doi.org/10.1016/j.cellsig.2026.112942","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"112942"},"PeriodicalIF":4.7,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243308","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}