Cellular signalling最新文献

{"title":"BCAR3 confers resistance to cisplatin in head and neck squamous cell carcinoma by sustaining TGF-β/SMAD signaling","authors":"Yaning Wang ,&nbsp;Zhenyu Cheng ,&nbsp;Rui Qiao ,&nbsp;Yixuan Zhao ,&nbsp;Hui Li ,&nbsp;Hongyu Zhao ,&nbsp;Qingguo Lai ,&nbsp;Teng Xu","doi":"10.1016/j.cellsig.2025.112124","DOIUrl":"10.1016/j.cellsig.2025.112124","url":null,"abstract":"<div><div>Cisplatin-based chemotherapy serves as a first-line therapy in advanced/metastatic head and neck squamous cell carcinoma (HNSCC). However, multiple factors confer treatment resistance, severely compromising its clinical efficacy. The purpose of this study was to determine the potential driving factors underlying this resistance and to develop a reliable combination treatment agent to overcome it. Using transcriptome analysis and clinical cohorts, breast cancer anti-estrogen resistance 3 (BCAR3) was identified as a candidate gene related to the development of intrinsic cisplatin resistance in HNSCC and was verified both in vitro and in vivo. Gene set enrichment analysis revealed that TGF-β/SMAD signaling was strongly activated in BCAR3-upregulated tumors. Western blotting and flow cytometry indicated that BCAR3 increased the phosphorylation of SMAD2 and facilitated the transcriptional activation of SMAD4, which suppressed mitochondria-derived apoptosis. Moreover, inhibition of TGF-β/SMAD signaling through treatment with galunisertib achieved synergistic efficacy with cisplatin. The above findings demonstrate that BCAR3 is a positive regulator of TGF-β/SMAD signaling-mediated intrinsic cisplatin resistance. Targeting the BCAR3/TGF-β/SMAD axis might be a promising therapeutic strategy for overcoming cisplatin resistance in HNSCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112124"},"PeriodicalIF":3.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039228","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":"Inhibition of ferroptosis rescues BMP osteogenic differentiation impaired by iron overload in the osteoporotic microenvironment","authors":"Xun Tang ,&nbsp;Mengfan Yang ,&nbsp;Yujiao Liu ,&nbsp;Hongjun Zhang ,&nbsp;Xiang Hong ,&nbsp;Meichao Deng ,&nbsp;Pei Liu ,&nbsp;Qing Sun ,&nbsp;Xiaolin Tu ,&nbsp;Gaohai Shao","doi":"10.1016/j.cellsig.2025.112116","DOIUrl":"10.1016/j.cellsig.2025.112116","url":null,"abstract":"<div><div>Bone morphogenetic proteins (BMPs) are effective for treating various orthopedic conditions and are widely used clinically. However, their therapeutic efficacy is limited in osteoporosis patients. Iron overload represents a key risk factor for osteoporosis, inducing ferroptosis and suppressing the osteogenic differentiation of bone marrow stromal cells (BMSCs). This mechanism likely contributes to the suboptimal response to BMP therapy in these patients. Using ovariectomized (OVX) mouse models and sequencing analysis of human BMSCs, we confirmed ferroptosis occurs in BMSCs from both OVX mice and osteoporosis patients, correlating with reduced BMP sensitivity. To investigate this, we established a BMP osteogenic differentiation model using C2C12 and ST2 cell lines, along with mouse and human primary BMSCs. Treatment with FK506 (tacrolimus) effectively activated BMP signaling and promoted osteogenic differentiation in this model. We then induced iron-overload conditions using ammonium ferric citrate (FAC). FAC triggered ferroptosis in stem cells, subsequently reducing BMP signaling and inhibiting osteogenic differentiation. Sequencing analysis further linked osteoporosis to downregulated Wnt signaling. Consequently, we administered melatonin (Mel) – previously shown by our group to activate Wnt signaling – to stem cells under FAC-induced iron overload and to OVX mice. Mel reduced ferroptosis in stem cells by restoring BMP signaling, promoted osteogenic differentiation, and increased bone mass in the mice. Our findings suggest ferroptosis is a key factor limiting BMP treatment efficacy in osteoporosis. Melatonin holds promise as an effective adjunct therapy to overcome this limitation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112116"},"PeriodicalIF":3.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032901","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":"Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells.","authors":"Chao Hu ,&nbsp;Tianhong Su ,&nbsp;Ying Zhang ,&nbsp;Jing Yang ,&nbsp;Xun Su ,&nbsp;Zhikang Zhang ,&nbsp;Xin Wang ,&nbsp;Weiwei Zou ,&nbsp;Dan Liang ,&nbsp;Yajing Liu ,&nbsp;Dongmei Ji ,&nbsp;Yunxia Cao","doi":"10.1016/j.cellsig.2025.112121","DOIUrl":"10.1016/j.cellsig.2025.112121","url":null,"abstract":"<div><div>Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G &gt; A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing OPA1-mediated fusion and enhancing DRP1-dependent fission, resulting in decreased expression of ND1, ND5, NDUFB8, SDHB and COX2, impaired mitochondrial bioenergetic function, and cell proliferation. Additionally, the m.3635G &gt; A mutation promoted intrinsic apoptosis, altered autophagic flux, evidenced by elevating levels in apoptotic proteins PARP1, caspase-3, and 9, reduced levels of autophagy protein LC3-II, and increased levels of substrate P62. Moreover, the m.3635G &gt; A mutation inhibited PINK1-Parkin-dependent mitophagy. Based on sex-specific differences in hormone metabolism, we proposed that estrogen plays a protective role in women and showed that estrogen receptor α and β were downregulated in LHON. We demonstrated that estradiol improved cell viability by reducing apoptosis, inducing mitochondrial biogenesis through the PGC1α-NRF1/2-TFAM axis, and vigorously promoting PINK1-Parkin-dependent mitophagy in LHON iPSCs and iPSC-derived RPE cells. Our findings have highlighted the critical role of the m.3635G &gt; A mutation in the pathogenetic process of LHON, and our observations support the hypothesis that estrogen is helpful in the preventive treatment of LHON.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112121"},"PeriodicalIF":3.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032878","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":"AID/HAT1-mediated epigenetic priming of JAG1/NOTCH signaling drives tumor microenvironment reprogramming in TNBC","authors":"Junna Jiao ,&nbsp;Zhuangwei Lv ,&nbsp;Kai Zhang ,&nbsp;Ruihan Wang ,&nbsp;Xiaoyu Shi ,&nbsp;Lulu Liu ,&nbsp;Junyue Jiao ,&nbsp;Yi'ang Niu ,&nbsp;Liwei Guo","doi":"10.1016/j.cellsig.2025.112118","DOIUrl":"10.1016/j.cellsig.2025.112118","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) presents a formidable therapeutic challenge due to its aggressive behavior, molecular heterogeneity, and lack of actionable targets. This study identifies activation-induced cytidine deaminase (AID) as a pivotal epigenetic driver reprogramming the tumor microenvironment (TME) via non-canonical regulation of NOTCH signaling. Mechanistically, AID recruits histone acetyltransferase 1 (HAT1) to form a chromatin-remodeling complex that binds the JAG1 promoter region (−1.5 kb to −1.1 kb), inducing H4K5 acetylation and transcriptional activation. This AID/HAT1-JAG1 axis amplifies NOTCH signaling in TNBC models, and genetic ablation of either AID or JAG1 suppresses malignant progression. Pharmacological disruption using 4-Deoxyuricine (AID antagonist) and MG149 (HAT1 inhibitor) reduces JAG1 acetylation, attenuates NOTCH signaling, and reshapes the TME by depleting AID/HAT1-JAG1 axis and enhancing the infiltration of T cells, NK cells, and B cells. Clinically, AID and JAG1 co-expression enhances immune cell infiltration in TME, which predicts poor survival in TNBC cohorts. Our findings redefine AID's role beyond its function in mediating mutagenesis, positioning it as a master epigenetic regulator of TNBC plasticity through acetylation-dependent NOTCH activation. These results resolve the paradox of NOTCH inhibitor resistance by identifying JAG1's epigenetic priming as a prerequisite for ligand-receptor signaling. Targeting the AID/HAT1-JAG1 axis offers a dual therapeutic strategy to overcome TME-mediated therapy resistance and provides a blueprint for precision immunotherapy in AID-positive TNBC subgroups.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112118"},"PeriodicalIF":3.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032848","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":"Endoplasmic reticulum stress regulates intestinal motility in acute pancreatitis by regulating the expression and phosphorylation of nNOS through IRE1α/XBP1s-PI3K/Akt signaling axis","authors":"Huan Liu ,&nbsp;Jie Cao ,&nbsp;Xingyou Li ,&nbsp;Chunxiang Zhang ,&nbsp;Cuiping Pan ,&nbsp;Shiwei Liang ,&nbsp;Haicheng Fang ,&nbsp;Ying Liu","doi":"10.1016/j.cellsig.2025.112123","DOIUrl":"10.1016/j.cellsig.2025.112123","url":null,"abstract":"<div><div>Intestinal dysmotility is a major complication that significantly impacts the prognosis of acute pancreatitis (AP). The neuronal nitric oxide synthase (nNOS) -expressing neurons within the enteric nervous system promote intestinal relaxation via the release of nitric oxide (NO). As the rate-limiting enzyme of NO synthesis, nNOS directly regulates NO production, thereby modulating intestinal motility. However, the upstream regulatory mechanisms involved in nNOS in intestinal dysmotility during AP remain unclear. In this study, we delved into the molecular mechanisms of intestinal motility regulation in AP through rats, enteric neuronal cells (ENCs), and intestinal smooth muscle cells (ISMCs). We found that the activation of PI3K/Akt pathway increased the protein expression of nNOS and its phosphorylation at Ser1417, and NO production in AP rats and LPS-stimulated ENCs. This led to reduced contractile activity and migratory capacity of ISMCs during co-culture and impaired intestinal smooth muscle strip contractile activity. Inhibition of PI3K/Akt pathway by LY294002 improved these effects. Further experiments demonstrated that during AP, endoplasmic reticulum stress (ERS) occurred within ENCs, manifested by endoplasmic reticulum expansion and activation of the IRE1α/XBP1s pathway. This promoted XBP1s binding to PI3K and Akt, activating this pathway and downstream effects. Inhibition of IRE1α/XBP1s pathway by toyocamycin further inhibited PI3K/Akt pathway and downstream effects. In conclusion, ERS in ENCs activates the IRE1α/XBP1s-PI3K/Akt signaling axis during AP, which upregulates the expression of nNOS and its phosphorylation at Ser1417, which increases NO production, and thus reduces the contractile activity and migratory capacity of ISMCs, ultimately causing intestinal dysmotility.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112123"},"PeriodicalIF":3.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032914","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 inhibitor of UHM splicing factors exerts anti-leukemic activity by altering cell cycle progression and reducing lysosome acidification","authors":"Mona Kazemi Sabzvar ,&nbsp;Eun Bee Cho ,&nbsp;Xinrui Yuan ,&nbsp;Arda Durmaz ,&nbsp;Amol D. Patil ,&nbsp;Daniel M. Collier ,&nbsp;Jianxiong Jiang ,&nbsp;Valeria Visconte ,&nbsp;Chao-Yie Yang","doi":"10.1016/j.cellsig.2025.112112","DOIUrl":"10.1016/j.cellsig.2025.112112","url":null,"abstract":"<div><div><strong>Mature mRNAs are generated by spliceosomes that recruit factors to aid RNA splicing in which introns are removed and exons joined. Among the splicing factors, a family of proteins contain a homologous</strong> U2 Auxiliary Factor (U2AF) Homology Motif (UHM) to <strong>bind with factors containing U2AF ligand motifs (ULM) and recruit them to regulate 3′ splice site selection. Mutations and overexpression of UHM splicing factors are frequently found in cancers. Although a few UHM inhibitors have been reported, their activities in cancer cells were not investigated. Here, we studied our recently discovered UHM inhibitor, SF-153, that targeted RBM39 and SPF45, and found SF-153 exerted anti-tumor activities in three leukemia cell lines. In the cell cycle and apoptosis analysis, SF-153 induces p53 mediated DNA damage response to give protracted S phase in NKM-1 but p53-independent G1 arrest in <em>p53</em></strong>^{<strong><em>null</em></strong>} <strong>K562 cells. RNA-seq analysis of NKM-1 treated with SF-153 revealed downregulation of Myc target genes and genes involved in nucleotides and protein synthesis. Western blot analysis confirmed decreased proteins levels of Myc, EEF1A1, and MCM7 suggesting reduced DNA replication activity in NKM-1. Transcript analysis derived from the RNA-seq data indicated six genes changed isoform patterns but downregulation of only one <em>DOCK2</em> isoform was confirmed in qRT-PCR. RNA-seq analysis additionally uncovered that SF-153 impaired lysosome acidification and inhibited autophagy to enhance the anti-leukemic activities. Taken together, our study characterized the multimodal mechanisms of inhibition by SF-153 in leukemia cells and laid the foundation for studying selective UHM inhibitors in future.</strong></div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112112"},"PeriodicalIF":3.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022869","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":"Lycium barbarum alleviates oxidative stress-induced ferroptosis and enhances mitophagy in intervertebral disc degeneration","authors":"Haicheng Dou ,&nbsp;Yutao Chen ,&nbsp;Jiaoxiang Chen ,&nbsp;Yuxuan Zhu ,&nbsp;Shu Yang ,&nbsp;Yingzhao Yan ,&nbsp;Yan Lin ,&nbsp;Sunli Hu","doi":"10.1016/j.cellsig.2025.112114","DOIUrl":"10.1016/j.cellsig.2025.112114","url":null,"abstract":"<div><div><em>Lycium barbarum</em> is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions, such as antioxidation, neuroprotection, and immune modulation. The therapeutic effect of <em>Lycium barbarum</em> on intervertebral disc degeneration (IVDD) has not been conclusively established. In our study, we investigated the mechanisms of <em>Lycium barbarum</em> extract (LBE) using Network pharmacology and bioinformatic analyses. In vitro experiments, the levels of ferroptosis were assessed using Western blot analysis and detection kits for MDA, Ferric iron and GSH. Transmission electron microscopy and Mitotracker were used to detect mitochondrial morphology. Immunofluorescence and Western blot were employed to detect the levels of mitophagy and lysosomal permeability. In vivo experiments, X-ray imaging, morphological staining, and immunohistochemical staining were used to assess the degree of intervertebral disc degeneration. As a result of the intersection between target genes of complex compounds and disease-related genes, 61 overlapping genes were identified, with PTGS2 ranking as the top overlapping gene. Molecular docking revealed that six compounds were highly stable in the Cys41 active site pocket of PTGS2. Moreover, LBE exhibited potential therapeutic effects through inhibiting mitochondrial dysfunction and ferroptosis. Besides, LBE can reduce lysosomal membrane permeability and enhance mitophagy caused by oxidative stress via regulating phosphatidylinositol metabolism. The administration of LBE in vivo can effectively slow the progression of intervertebral disc degeneration. The findings of this study suggest that LBE exhibits maybe a potential therapeutic candidate for intervertebral disc degeneration.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112114"},"PeriodicalIF":3.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023000","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":"Dual role of mir-146a in non-small cell lung cancer progression: Molecular mechanisms and clinical potential","authors":"Mina Alimohammadi ,&nbsp;Davar Amani ,&nbsp;Ian M Adcock ,&nbsp;Esmaeil Mortaz","doi":"10.1016/j.cellsig.2025.112115","DOIUrl":"10.1016/j.cellsig.2025.112115","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality. 2.48 million new cases were reported globally in 2022, driven by rising adenocarcinoma rates linked to environmental factors such as air pollution. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by targeting messenger RNA for degradation or translational repression. Emerging studies highlight miR-146a as a molecular pivot with dual functionality that acts as a tumor suppressor by inhibiting NF-κB signaling to reduce inflammation and chemoresistance while paradoxically exhibiting oncogenic potential through immune modulation in specific microenvironments. The expression of miR-146a has been associated with numerous pathological and physiological alterations in cancer cells, including the modulation of various signaling pathways such as TNF-α, NF-κB, MEK-1/2, and JNK-1/2. miR-146a can act exogenously through extracellular vesicles and thereby reprogram tumor-associated macrophages to either promote or inhibit metastasis depending on cellular context. The diagnostic potential of miR-146a is underscored by expression patterns correlating with disease progression and treatment response in NSCLC, whilst preclinical studies suggest therapeutic promise when combined with checkpoint inhibitors. In this review, we first discuss the biogenesis and function of miR-146a in NSCLC development, with emphasis on recent findings that underscore the dual role of miR-146a in the regulation of cell proliferation, invasion, inflammation, immune responses, and chemoresistance in NSCLC. We also describe the possible function of miR-146a as a biomarker for cancer diagnosis, prognosis, and therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112115"},"PeriodicalIF":3.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022986","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":"HCN2 promotes neurodevelopmental and synaptic function repair through the CaMKII/CREB pathway to alleviate general anesthesia-induced cognitive impairment","authors":"Lei Yang ,&nbsp;Xiao'e Cheng ,&nbsp;Lingling Ye ,&nbsp;Yinqi Shi ,&nbsp;Changsheng Ye ,&nbsp;Fusheng Wei","doi":"10.1016/j.cellsig.2025.112113","DOIUrl":"10.1016/j.cellsig.2025.112113","url":null,"abstract":"<div><div>Repeated exposure to gestational general anesthesia during pregnancy has been associated with neurodevelopmental damage and cognitive and social dysfunction in offspring. This study investigates the underlying mechanisms and therapeutic strategies for mitigating these effects. Behavioral tests revealed significant impairments in cognitive, social, and spatial learning abilities in the offspring of general anesthesia-treated mice, alongside delayed eye-opening, reduced body weight, and neuronal damage. Mechanistic analyses showed that general anesthesia exposure disrupted ionic homeostasis, reduced hyperpolarization-activated cyclic nucleotide-gated channel (HCN) expression, and suppressed the calcium/calmodulin-dependent protein kinase II (CaMKII)/cAMP-response element-binding (CREB) protein signaling pathway, leading to synaptic dysfunction and impaired neuronal activity. Therapeutic strategies using adeno-associated virus (AAV)-mediated HCN2 overexpression restored HCN2 expression, improved ionic homeostasis, and reactivated the CaMKII/CREB signaling pathway, significantly ameliorating cognitive, social, and synaptic deficits. In vitro, lentivirus-HCN2 overexpression rescued disrupted sodium and potassium levels, synaptic protein expression (synaptophysin and brain-derived neurotrophic factor), and protein kinase A activity. However, these improvements were attenuated when CaMKII or CREB functions were inhibited, highlighting their critical roles in HCN2-mediated neural regulation. In vivo, AAV-HCN2 and AAV-CREB therapies improved neuronal activity, synaptic integrity, and behavioral outcomes in general anesthesia-exposed offspring, while CaMKII inhibition exacerbated developmental and behavioral abnormalities. These findings demonstrate that HCN2 improves neural function, synaptic plasticity, and behavior through the CaMKII/CREB signaling pathway. This study provides new insights into potential therapeutic strategies for neurodevelopmental damage caused by repeated general anesthesia exposure.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112113"},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008191","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":"Mechanistic study of the Tβ4/SLC7A11 signaling pathway regulating breast cancer evolution","authors":"Zhaoyan Jin ,&nbsp;Hongshu Li ,&nbsp;Jiafeng Li ,&nbsp;Ying Chang ,&nbsp;Zhengri Piao ,&nbsp;Quanxin Jin ,&nbsp;Tiefeng Jin","doi":"10.1016/j.cellsig.2025.112111","DOIUrl":"10.1016/j.cellsig.2025.112111","url":null,"abstract":"<div><div>Thymosin β4 (Tβ4) plays a critical role in breast cancer progression, yet its molecular mechanism remains unclear. In this study, we identified that Tβ4 is significantly upregulated in breast cancer tissues and cell lines, and its high expression correlates with poor clinical outcomes. Functionally, Tβ4 promotes breast cancer cell proliferation, migration, epithelial–mesenchymal transition (EMT), and angiogenesis while inhibiting apoptosis. Mechanistically, Tβ4 directly regulates the expression of SLC7A11, a key cystine/glutamate antiporter, thereby enhancing glutathione biosynthesis and suppressing lipid peroxidation to inhibit ferroptosis. Rescue experiments further demonstrated that silencing SLC7A11 abrogates the oncogenic effects of Tβ4 both in vitro and in vivo. Collectively, these findings uncover a novel Tβ4/SLC7A11 axis that modulates ferroptosis sensitivity and contributes to breast cancer malignancy, offering potential therapeutic implications for targeting ferroptosis resistance.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"136 ","pages":"Article 112111"},"PeriodicalIF":3.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005971","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}