Cell Communication and Signaling最新文献

{"title":"Correction: Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under chronic stress.","authors":"Jinxin Lu, Xiaoyu Zhang, Keyu Su, Huandong Luo, Congcong Liu, Yuqing Yang, Bin He, Cenxin Wang, Zhuoran Zhao, Xianxian Liu, Xu Wang, Peixuan Meng, Dekang Lv, Chunli Wang, Keith W Kelley, Ling Wang, Bai Cui, Quentin Liu, Fei Peng","doi":"10.1186/s12964-026-03056-y","DOIUrl":"10.1186/s12964-026-03056-y","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"24 1","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.","authors":"Haixia Wang, Ruiming Wen, Emily Parker, Luodan Yang","doi":"10.1186/s12964-026-03083-9","DOIUrl":"10.1186/s12964-026-03083-9","url":null,"abstract":"<p><p>Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2R: a new player in the IGF2 loop sustaining adrenocortical carcinogenesis.","authors":"Emma Nozza, Emanuela Esposito, Sonia Di Bari, Rosa Catalano, Genesio Di Muro, Anna Maria Barbieri, Elisa Cassinotti, Serena Palmieri, Alessandra Mangone, Valentina Morelli, Mariangela Tamburello, Constanze Hantel, Laura-Sophie Landwehr, Guido Di Dalmazi, Emanuele Ferrante, Giovanna Mantovani, Erika Peverelli","doi":"10.1186/s12964-026-03057-x","DOIUrl":"10.1186/s12964-026-03057-x","url":null,"abstract":"<p><strong>Background: </strong>Most of adrenocortical carcinomas (ACC) are characterized by IGF2 overexpression; therefore, several studies have focused on its two oncogenic effectors, the tyrosine-kinase receptors IGF1R and IR. However, the specific IGF2 receptor, IGF2R, due to its scavenging activity, was considered a tumour suppressor and has never been fully investigated in this context. Nevertheless, recent evidence from other tumours identified IGF2R as a pro-tumorigenic actor able to exert its function through the downstream activation of the pro-mitotic sphingosine kinases (SphK) enzymes responsible for sphingosine phosphorylation. Hence, the main aims of this study were to elucidate the role of IGF2R in ACC cells, investigate its action mechanism, and test IGF2R and SphK inhibitors as possible novel therapies for ACC.</p><p><strong>Methods: </strong>The present study was conducted in vitro in 4 different ACC cell lines and in 3 ACC primary cultures, to reflect the heterogeneity of ACC. Target protein and transcript expression were evaluated on normal and tumoral adrenal tissues and cell lines, while the effects of IGF2R downregulation and overexpression, along with IGF2R and SphK inhibition, were tested on cell viability, proliferation, and apoptosis as well as cortisol secretion.</p><p><strong>Results: </strong>ACC tissue analysis demonstrated the IGF2R overexpression compared to normal adrenal cortex, which was also positively correlated with IGF2 and IGF1R expression in ACC. In vitro assays proved the pro-mitotic involvement of IGF2R and its role in the downstream activation of SphK. Finally, we observed the anti-tumoral efficacy of three different inhibitors of this pathway on ACC cell lines and primary cultures: a specific neutralizing anti-IGF2R antibody was tested for its anti-proliferative action, while two SphK inhibitors, safingol (SAF) and fingolimod (FTY), were able to decrease cell proliferation, viability, and cortisol secretion, while promoting cell apoptosis.</p><p><strong>Conclusions: </strong>Overall, this comprehensive in vitro evaluation of the role of IGF2R in ACC demonstrates its tumorigenic effect through SphK activation. Moreover, the three pharmacological strategies here employed successfully controlled in vitro ACC growth, suggesting IGF2R/SphK pathway represents a novel therapeutic target for ACC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing tumor-associated exosomal aminopeptidase N as a dual-function tool for monitoring and tackling chemoresistance in gastric cancer.","authors":"Wangyu Cai, Zheru Ma, Wen Xie, Ende Lin, Shengyuan Zheng, Lingyun Lin, Yuanyuan Xie, Zinan Dong, Peiyu Lv, Jia Cheng, Li Yang, Xiaoteng Fu, Fuxing Zhang, Zengpeng Li, Lin Wang","doi":"10.1186/s12964-026-03079-5","DOIUrl":"10.1186/s12964-026-03079-5","url":null,"abstract":"<p><p>Chemoresistance remains a major obstacle to effective treatment in gastric cancer (GC), with a notable scarcity of clinically applicable biomarkers and therapeutic targets. In this study, we employed an integrated proteomic approach analyzing paired serum samples from GC patients at disease control and progressive disease stages during chemotherapy, exosomes from chemoresistant and chemosensitive GC cells, and corresponding whole-cell proteomes to identify tumor-associated exosomal drivers of chemoresistance. Cross-dataset integration identified aminopeptidase N (APN/CD13) as selectively enriched under chemoresistant conditions. Functional validation demonstrated that APN depletion via shRNA or CRISPR restored cisplatin sensitivity in refractory cells, whereas APN overexpression conferred chemoprotection. A neutralizing anti-APN monoclonal antibody resensitized resistant cells and showed superior efficacy compared with the broad-spectrum peptidase inhibitor bestatin in vivo. Mechanistically, APN sustained a ferroptosis-suppressive state: its inhibition increased ROS and lipid peroxidation, shifted transcriptomic profiles toward pro-ferroptotic pathways, and downregulated the lipid peroxide detoxifier AKR1C2, which correlated with poor prognosis and APN expression in the TCGA-STAD cohort. Exosomal transfer assays confirmed that APN-enriched vesicles disseminated chemoresistance and ferroptosis evasion to sensitive cells, accelerating tumor progression during chemotherapy, whereas APN-deficient exosomes lacked this capacity. Clinically, serum exosomal APN levels robustly distinguished progressive disease from disease control in a cohort of 105 patients (AUC = 0.85; optimal cutoff 0.936 ng/mL). Collectively, these findings position exosomal APN as a dual-function tool, serving both as a dynamic liquid biopsy biomarker and an antibody-targetable node for monitoring and overcoming chemoresistance in gastric cancer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkinson's disease as a multi-axis systems disorder: integrating molecular pathology and circuit-level therapeutics.","authors":"Duc-Hiep Bach, Thanh Liem Nguyen","doi":"10.1186/s12964-026-03089-3","DOIUrl":"10.1186/s12964-026-03089-3","url":null,"abstract":"<p><p>Parkinson's disease (PD) has generated extensive mechanistic insight, yet nearly all candidate disease-modifying therapies have failed in clinical trials. Antibodies targeting α-synuclein, mitochondrial antioxidants, lysosomal interventions, and anti-inflammatory agents frequently achieve target engagement without slowing clinical progression, creating a central paradox in PD therapeutics.Here we propose that this discrepancy arises because PD is not primarily a single-pathway neurodegenerative disorder but a multi-scale systems disease. Molecular pathology, organellar dysfunction, immune activation, and large-scale network instability form a self-reinforcing cascade in which interventions acting at a single biological level cannot substantially modify disease once degeneration is embedded within distributed neural circuits.This framework generates testable predictions: pathway-targeted therapies may show benefit primarily in prodromal or biomarker-defined populations, whereas established clinical PD will likely require combination strategies coupling circuit restoration with axis-matched molecular interventions. Therapeutic responsiveness should therefore correlate more strongly with network integrity than with target engagement alone.Viewing PD as a multi-scale systems disorder provides a unifying explanation for repeated therapeutic failures and offers a framework for biomarker-guided, stage-matched disease-modifying trials.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.","authors":"Karthik Reddy Kami Reddy, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Aaditya Krishna Arun, Sachin B Jorvekar, Yongchao Dou, Mohammed Khurshidul Hassan, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Jun Xu, Daniel Kraushaar, Adriana Langer Gramer, Allison C Bellman, Leomar Y Ballester, Yuan Xu, Robert Taylor Ripley, Seth P Lerner, Roni J Bollag, Martha K Terris, Chong-Xian Pan, Benny Abraham Kaipparettu, Yair Lotan, Nagireddy Putluri","doi":"10.1186/s12964-026-03058-w","DOIUrl":"10.1186/s12964-026-03058-w","url":null,"abstract":"<p><strong>Background: </strong>Genomic analysis has revealed that approximately 40% of bladder cancer (BLCA) tumors harbor alterations in the PI3K/AKT pathway, with PIK3CA mutations occurring in 15-25% of cases. PIK3CA, which encodes the catalytic p110α subunit of PI3K, plays a critical role in regulating cell survival, proliferation, and metabolism. However, the metabolic and functional consequences of PIK3CA mutations in BLCA remain poorly defined.</p><p><strong>Methods: </strong>To investigate the role of PIK3CA mutations in BLCA, we performed targeted sequencing on tumors from patients, identifying recurrent alterations. Using CRISPR/Cas9 knock-in models in SCaBER and UM-UC-3 cell lines, we introduced the PIK3CA E545K mutation to study its effects. We conducted transcriptomic profiling, targeted metabolomics, and stable isotope tracing to assess metabolic reprogramming. Functional assays measured proliferation, mitochondrial complex I activity, and glutaminolysis. Orthotopic xenografts in mice were used to evaluate in vivo tumor growth and metabolism.</p><p><strong>Results: </strong>PIK3CA mutations were present in 20% of cases, consistent with TCGA data. The E545K and E545Q hotspots accounted for 70% of these mutations. PIK3CA E545K strongly activated PI3K/AKT signaling. Transcriptomic analysis revealed enrichment of OXPHOS, fatty acid metabolism, and mTORC1 signaling. Metabolomics indicated changes in TCA cycle metabolites and enhanced reductive carboxylation of glutamine to citrate, driving fatty acid synthesis. Mutant cells showed increased expression of GLS1 and FASN, higher proliferation rates, and elevated mitochondrial complex I activity. In vivo, PIK3CA-mutant xenografts displayed significantly increased tumor growth.</p><p><strong>Conclusion: </strong>PIK3CA mutations are frequent drivers of metabolic reprogramming in BLCA, leading to increased glutamine flux, elevated OXPHOS activity, and enhanced fatty acid synthesis, all of which contribute to tumor progression. These findings provide the first comprehensive evidence that PIK3CA-driven metabolic alterations are both biomarkers of aggressive disease and actionable therapeutic targets. The efficacy of PI3Kα inhibition in combination with metabolic targets may support its potential in precision medicine for PIK3CA-mutant BLCA and highlights the value of integrating metabolic biomarkers into treatment strategies for advanced BLCA.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ROS/HIF-1α/JMY signaling axis drives radiation-induced migration and invasion of neural progenitor cells.","authors":"Oriane Bergiers, Hayet Bensalah-Pigeon, Oscar Gitton-Quent, Karim Ben M'Barek, Mahasen Saati, Christine Granotier-Beckers, Olivier Etienne, Delphine Moison, Guillaume Piton, Didier Busso, Marie-Justine Guerquin, Jose R Pineda, François D Boussin, Laurent R Gauthier","doi":"10.1186/s12964-026-03025-5","DOIUrl":"https://doi.org/10.1186/s12964-026-03025-5","url":null,"abstract":"<p><strong>Background: </strong>Neural progenitor cell (NPC) migration is essential for proper cortical development, and its disruption contributes to severe brain malformations such as lissencephaly, polymicrogyria, and microcephaly. Although abnormal neuronal migration has been reported in irradiated embryos, the molecular mechanisms by which ionizing radiation affects NPC motility remain poorly understood.</p><p><strong>Methods: </strong>Fetal human and mouse NPCs were exposed to low doses of ionizing radiation (0.5-3 Gy). Migratory and invasive properties were assessed both in vitro and in vivo. Reactive oxygen species (ROS) production was monitored shortly after irradiation, and downstream signaling pathways were investigated through analysis of HIF-1α nuclear accumulation and expression of Junction-mediating and regulatory protein (JMY). Functional involvement of HIF-1α and JMY was tested using pharmacological or molecular inhibition approaches.</p><p><strong>Results: </strong>Ionizing radiation rapidly enhanced the migratory and invasive capacity of fetal human and mouse NPCs in vitro and in vivo. This response was preceded by an early increase in endogenous ROS, which initiated the migratory phenotype. Mechanistically, radiation-induced ROS promoted nuclear accumulation of HIF-1α, leading to upregulation of JMY, an actin nucleation-promoting factor that drives cytoskeletal remodeling and cell motility. Inhibition of either HIF-1α or JMY abolished the radiation-induced increase in NPC migration and invasion, identifying a conserved ROS/HIF-1α/JMY signaling axis as a key mediator of this effect.</p><p><strong>Conclusions: </strong>These findings reveal that low-dose ionizing radiation stimulates NPC migration and invasion through activation of a ROS/HIF-1α/JMY pathway. Given the critical requirement for tightly regulated NPC migration during brain morphogenesis, aberrant activation of this signaling axis may contribute to radiation-induced neurodevelopmental disorders.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450596","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":"Free mitochondrial transfer enhances bone regeneration through cathepsin H mediated cysteine cycle.","authors":"Jiayong Diao, Qixuan He, Quanzhen Liu, Yuxuan Liu, Simiao Chen, Yuzhe Zhang, Houda Gui, Jingyi Chen, Dongni Wu, Xinyu Pang, Qingyue Zhang, Ya-Nan Wang, Dongjiao Zhang","doi":"10.1186/s12964-026-03060-2","DOIUrl":"10.1186/s12964-026-03060-2","url":null,"abstract":"<p><strong>Background: </strong>Mitochondria, as crucial organelles in eukaryotic cells, are deeply involved in cellular energy metabolism and biogenesis. Currently, mitochondria have been found to transfer between cells and regulate a range of cellular functions and research has found that mitochondrial transfer has been shown to play an important role in regulating bone homeostasis.</p><p><strong>Methods: </strong>Laser confocal imaging was used to confirm the occurrence of mitochondrial transfer between cells. JC-1 staining explains the state of free mitochondria in receptor cells. In order to reveal the relationship between the state and function of free mitochondria, osteogenic induction, Western blotting, flow cytometry, and in vivo experiments were conducted. RNA seq is used to analyze changes in cells. Different inhibitors were used to verify the specific mechanism of action of free mitochondrial transfer.</p><p><strong>Results: </strong>Free mitochondrial transfer can improve the function of receptor cells through lysosomal pathway. Free mitochondria are degraded by cathepsin H (Ctsh) in lysosomes and release a large amount of cysteine after entering the receptor cells. In this process, the existence of membrane potential of free mitochondria is not critical. Cysteine, as the most important raw material for glutathione synthesis, can enhance the number and function of mitochondria in receptor cells.</p><p><strong>Conclusion: </strong>Our study demonstrates that free mitochondrial transfer promotes bone regeneration by increasing cysteine supply, and provides innovative insights for understanding mitochondrial transfer.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DEPDC7 couples homologous chromosome segregation to asymmetric cytokinesis through recruiting ARP2/3 complex in oocyte meiosis.","authors":"Jia-Ni Guo, Si-Min Sun, Xue-Mei Yang, Chao Jiang, Yi-Ke Lu, Yuan-Hong Xu, Bing-Wang Zhao, Zhen-Bo Wang","doi":"10.1186/s12964-026-03068-8","DOIUrl":"10.1186/s12964-026-03068-8","url":null,"abstract":"<p><p>During mammal meiosis, proper cytokinesis is essential for oocyte maturation. This process depends on actin cap formation and cortical polarity establishment. In this study, we reported that DEP domain-containing protein 7 (DEPDC7) functioned as a regulator of oocyte cytokinesis. Conditional knockout of DEPDC7 in oocytes resulted in triploid zygotes, impaired early embryo development, and ultimately led to female subfertility. Chromosome spread analysis showed that superovulated oocytes lacking DEPDC7 were diploid. Although the assembly and migration of the spindles were normal in DEPDC7-deleted oocytes during meiosis I, actin cap assembly and first polar body extrusion were severely disrupted. Furthermore, we found that DEPDC7 colocalized and interacted with ARP2/3 complex, regulating its subcortical enrichment. Taken together, our findings reveal the function of DEPDC7 is required for polarity establishment and coupling chromosome segregation to cytokinesis during mouse oocyte meiosis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual targeting of interlocked PTK2B and MAPK signaling triggers synergistic ferroptosis via autophagic flux disruption in BRAF^V600E glioma.","authors":"Min Wang, Chengyan Xu, Shanshan Xie, Jichen Jin, Pengqi Zhang, Jiyong Liu, Cheng Wu, Yongmei Xi, Xiaohang Yang","doi":"10.1186/s12964-026-03045-1","DOIUrl":"10.1186/s12964-026-03045-1","url":null,"abstract":"<p><strong>Background: </strong>BRAF^V600E mutation is one of the most common oncogenic drivers in gliomas, sharing the highest incidence in pediatric low-grade gliomas (~ 20%) and being frequently associated with poor prognosis. Although combination therapies targeting both BRAF^V600E and downstream MAPK signaling have been developed, their efficacy is substantially limited by acquired drug resistance. Consequently, identifying the underlying mechanisms of resistance and novel therapeutic vulnerabilities remains an urgent need.</p><p><strong>Methods: </strong>Using patient gene expression profiles, immunohistochemistry on glioma samples, glioma cell lines, and a Drosophila glioma model, we identified Protein Tyrosine Kinase 2 Beta (PTK2B) as a druggable vulnerability in BRAF^V600E glioma. Loss-of-function studies were achieved by PTK2B knockdown in DBTRG-05MG cells and Fak knockout in Drosophila, assessing effects on tumor survival/proliferation. The underlying signaling mechanisms were investigated using RNA sequencing, proteomics and a suite of assays (e.g., Western blot, immunofluorescence, flow cytometry). Finally, the reciprocal compensatory mechanism between PTK2B and MAPK signaling was established in both cellular and Drosophila models, and the synergistic effect of their co-inhibition was validated in DBTRG-05MG and AM-38 cells.</p><p><strong>Results: </strong>PTK2B and its Drosophila orthologue Focal adhesion kinase (Fak) are highly expressed in BRAF^V600E/dRaf^GOF glioma, and their inhibition significantly suppresses tumor growth. Our studies revealed that PTK2B knockdown triggers potent ferroptosis in glioma cells through endoplasmic reticulum stress-induced autophagic flux disruption, a mechanism which is partially overlapped with the cell death induced by MAPK signaling inhibition. We uncovered the interlocking mechanism between highly expressed PTK2B and hyperactive MAPK signaling in BRAF^V600E glioma, wherein suppression of either one prompts compensatory upregulation of the other, thereby attenuating tumor cell death under the stress. Simultaneous inhibition of PTK2B and MAPK signaling achieves strong synergistic anti-tumor effect, highlighting the therapeutic promise of this combination strategy.</p><p><strong>Conclusions: </strong>Our findings establish PTK2B as a critical regulator and co-targetable vulnerability in BRAF^V600E glioma. We delineate a novel interlocking mechanism wherein PTK2B and MAPK engage in reciprocal negative feedback regulation, enabling adaptive resistance. This work provides a compelling mechanistic rationale for co-targeting PTK2B and MAPK to disrupt this survival axis and overcome therapeutic resistance.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":11.6,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148438999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}