Pub Date : 2026-01-05DOI: 10.1038/s41392-025-02501-7
Young Joo Jeon,Ze'ev A Ronai
The endoplasmic reticulum (ER) is a major cellular organelle for the synthesis and folding of secretory and transmembrane proteins, whose proper function underpins organellar homeostasis, proper tissue function, and organismal physiology. Protein quality control (PQC) systems at the ER include the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy, which monitor ER homeostasis and contribute to protein refolding, sequestration, or degradation. ERAD prevents the accumulation of misfolded or orphan proteins that would otherwise be toxic. By controlling the degradation of these proteins, ERAD performs a core function in governing adaptation to proteotoxic stress. ERAD also regulates the abundance of folding-competent proteins as a means to fine-tune key physiological processes. Among its complex regulatory activities, ERAD controls cellular processes such as lipid homeostasis, calcium flux, and cell fate decisions, which are all required for the maintenance of organelle homeostasis. Highlighting its importance, dysregulation of ERAD often results in devastating diseases. Here, we discuss the molecular and mechanistic understanding of protein quality and quantity control by ERAD and its interface with ER-phagy, as well as other cellular stress programs. The implications of ERAD and its associated regulatory arms for cellular homeostasis, its effects on health and disease, and current therapeutic approaches are discussed.
{"title":"The role of ER-associated degradation and ER-phagy in health and disease.","authors":"Young Joo Jeon,Ze'ev A Ronai","doi":"10.1038/s41392-025-02501-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02501-7","url":null,"abstract":"The endoplasmic reticulum (ER) is a major cellular organelle for the synthesis and folding of secretory and transmembrane proteins, whose proper function underpins organellar homeostasis, proper tissue function, and organismal physiology. Protein quality control (PQC) systems at the ER include the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy, which monitor ER homeostasis and contribute to protein refolding, sequestration, or degradation. ERAD prevents the accumulation of misfolded or orphan proteins that would otherwise be toxic. By controlling the degradation of these proteins, ERAD performs a core function in governing adaptation to proteotoxic stress. ERAD also regulates the abundance of folding-competent proteins as a means to fine-tune key physiological processes. Among its complex regulatory activities, ERAD controls cellular processes such as lipid homeostasis, calcium flux, and cell fate decisions, which are all required for the maintenance of organelle homeostasis. Highlighting its importance, dysregulation of ERAD often results in devastating diseases. Here, we discuss the molecular and mechanistic understanding of protein quality and quantity control by ERAD and its interface with ER-phagy, as well as other cellular stress programs. The implications of ERAD and its associated regulatory arms for cellular homeostasis, its effects on health and disease, and current therapeutic approaches are discussed.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":"7"},"PeriodicalIF":39.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells. Although targeted therapies have improved outcomes, resistance remains a challenge, particularly in high-risk patients with TP53 mutations or unmutated immunoglobulin heavy-chain variable region (IGHV) genes (U-CLL). Ferroptosis, a regulated, iron-dependent form of cell death, may represent an exploitable vulnerability in CLL; however, its mechanisms and clinical relevance remain poorly understood. Here, we identified IGHV status and microenvironmental cues as determinants of ferroptosis sensitivity. Using CLL cell lines, patient samples, and in vivo models, we show that CLL cells exhibit elevated basal levels of lipid peroxides and labile iron, predisposing them to ferroptosis. However, stromal interactions enhance cystine import and glutathione synthesis, thereby mitigating susceptibility to ferroptosis. Mechanistically, BTK inhibition sensitizes CLL cells to ferroptosis by increasing the transferrin receptor (TFRC, CD71) and increasing the intracellular Fe²⁺ level. High TFRC expression was associated with improved survival in two independent CLL patient cohorts, supporting its therapeutic and prognostic relevance. Combining ibrutinib with the GPX4 inhibitor RSL3 enhances ferroptosis and improves antileukemic efficacy in vivo. CLL cells with mutated IGHV genes (M-CLL) display greater TFRC expression and ferroptosis sensitivity than U-CLL cells do. This resistance can be overcome by ibrutinib-mediated TFRC induction or via metabolic targeting of fatty acid metabolism. Notably, ACSL1 is selectively upregulated in U-CLL cells and represents a targetable metabolic enhancer of ferroptosis sensitivity, as shown in vivo. Our findings reveal that TFRC and ACSL1 are functionally distinct yet targetable nodes that govern ferroptosis vulnerability in CLL patients and may guide novel therapeutic strategies for high-risk patients.
{"title":"Immunoglobulin heavy-chain status and stromal interactions shape ferroptosis sensitivity in chronic lymphocytic leukemia.","authors":"Martin Böttcher,Lea Reemts,Paul J Hengeveld,Romy Böttcher-Loschinski,Vikas Bhuria,Junyan Lu,Silvia Materna-Reichelt,Durdam Das,Natasa Stojanović Gužvić,Heiko Bruns,Wolfgang Huber,Thorsten Zenz,Denny Schanze,Martin Zenker,Sascha Dietrich,Anton W Langerak,Dimitrios Mougiakakos","doi":"10.1038/s41392-025-02535-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02535-x","url":null,"abstract":"Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells. Although targeted therapies have improved outcomes, resistance remains a challenge, particularly in high-risk patients with TP53 mutations or unmutated immunoglobulin heavy-chain variable region (IGHV) genes (U-CLL). Ferroptosis, a regulated, iron-dependent form of cell death, may represent an exploitable vulnerability in CLL; however, its mechanisms and clinical relevance remain poorly understood. Here, we identified IGHV status and microenvironmental cues as determinants of ferroptosis sensitivity. Using CLL cell lines, patient samples, and in vivo models, we show that CLL cells exhibit elevated basal levels of lipid peroxides and labile iron, predisposing them to ferroptosis. However, stromal interactions enhance cystine import and glutathione synthesis, thereby mitigating susceptibility to ferroptosis. Mechanistically, BTK inhibition sensitizes CLL cells to ferroptosis by increasing the transferrin receptor (TFRC, CD71) and increasing the intracellular Fe²⁺ level. High TFRC expression was associated with improved survival in two independent CLL patient cohorts, supporting its therapeutic and prognostic relevance. Combining ibrutinib with the GPX4 inhibitor RSL3 enhances ferroptosis and improves antileukemic efficacy in vivo. CLL cells with mutated IGHV genes (M-CLL) display greater TFRC expression and ferroptosis sensitivity than U-CLL cells do. This resistance can be overcome by ibrutinib-mediated TFRC induction or via metabolic targeting of fatty acid metabolism. Notably, ACSL1 is selectively upregulated in U-CLL cells and represents a targetable metabolic enhancer of ferroptosis sensitivity, as shown in vivo. Our findings reveal that TFRC and ACSL1 are functionally distinct yet targetable nodes that govern ferroptosis vulnerability in CLL patients and may guide novel therapeutic strategies for high-risk patients.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"4 1","pages":"3"},"PeriodicalIF":39.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcriptional reprogramming, contribute to T cell dysfunction. Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity. These therapeutic strategies include immune checkpoint inhibition, cytokine therapies, metabolic reprogramming, and cell-based therapies. Despite these advancements, reversing T cell exhaustion presents several challenges, such as individual variability, resistance, and potential side effects. Furthermore, accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas. This review provides an overview of the history and milestones in T cell exhaustion research; summarizes the mechanisms of T cell exhaustion and its implications in cancer, chronic infections, and autoimmune diseases; discusses advancements and challenges in emerging therapies; and explores future research directions aimed at improving T cell function and enhancing immune responses.
{"title":"Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion","authors":"Yiran Wu, Yuchen Wu, Zhengyu Gao, Weixing Yu, Long Zhang, Fangfang Zhou","doi":"10.1038/s41392-025-02327-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02327-3","url":null,"abstract":"T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcriptional reprogramming, contribute to T cell dysfunction. Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity. These therapeutic strategies include immune checkpoint inhibition, cytokine therapies, metabolic reprogramming, and cell-based therapies. Despite these advancements, reversing T cell exhaustion presents several challenges, such as individual variability, resistance, and potential side effects. Furthermore, accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas. This review provides an overview of the history and milestones in T cell exhaustion research; summarizes the mechanisms of T cell exhaustion and its implications in cancer, chronic infections, and autoimmune diseases; discusses advancements and challenges in emerging therapies; and explores future research directions aimed at improving T cell function and enhancing immune responses.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"17 1","pages":"2"},"PeriodicalIF":39.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1038/s41392-025-02499-y
Enrique Rozengurt, Guido Eibl
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which there is no effective treatment. A deep understanding of the mechanisms underlying the molecular pathogenesis, signaling pathways and risk factors leading to PDAC is of paramount importance for identifying novel targets, prognostic markers, preventive strategies, and signature markers for use in specific and personalized therapeutic procedures. Activating somatic mutations in the KRAS oncogene play a critical role in PDAC initiation and maintenance. Here, we highlight the complex interplay between KRAS signaling, the transcriptional coactivator YES1-associated protein (YAP) and Src family kinases (SFKs) in the pathogenesis of PDAC and drug sensitivity. We subsequently focused on diet-induced obesity, which has been correlated with an increased risk for developing PDAC in humans and mice and more severe clinical outcomes. Accumulating evidence also indicates that neural signals regulate critical functions of cancer cells, including their proliferation and dissemination, and that chronic stress promotes PDAC through the sympathetic nervous system via β-adrenergic receptors expressed by PDAC cells and other cells in the tumor microenvironment. Obesogenic mediators and stress neurotransmitters stimulate protein kinases, including PKA and PKD, which converge on CREB/ATF1 phosphorylation in PDAC cells. Since stress and obesity cooperate to promote the progression of PDAC, novel combinatorial strategies to prevent this devastating disease could be developed, repositioning FDA-approved drugs that are extensively used to treat cardiovascular and metabolic disorders and diseases. Finally, we review new advances in the treatment of PDAC, focusing on the discovery of novel drugs that directly inhibit KRAS and YAP function.
{"title":"Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies","authors":"Enrique Rozengurt, Guido Eibl","doi":"10.1038/s41392-025-02499-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02499-y","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which there is no effective treatment. A deep understanding of the mechanisms underlying the molecular pathogenesis, signaling pathways and risk factors leading to PDAC is of paramount importance for identifying novel targets, prognostic markers, preventive strategies, and signature markers for use in specific and personalized therapeutic procedures. Activating somatic mutations in the <jats:italic>KRAS</jats:italic> oncogene play a critical role in PDAC initiation and maintenance. Here, we highlight the complex interplay between KRAS signaling, the transcriptional coactivator YES1-associated protein (YAP) and Src family kinases (SFKs) in the pathogenesis of PDAC and drug sensitivity. We subsequently focused on diet-induced obesity, which has been correlated with an increased risk for developing PDAC in humans and mice and more severe clinical outcomes. Accumulating evidence also indicates that neural signals regulate critical functions of cancer cells, including their proliferation and dissemination, and that chronic stress promotes PDAC through the sympathetic nervous system via β-adrenergic receptors expressed by PDAC cells and other cells in the tumor microenvironment. Obesogenic mediators and stress neurotransmitters stimulate protein kinases, including PKA and PKD, which converge on CREB/ATF1 phosphorylation in PDAC cells. Since stress and obesity cooperate to promote the progression of PDAC, novel combinatorial strategies to prevent this devastating disease could be developed, repositioning FDA-approved drugs that are extensively used to treat cardiovascular and metabolic disorders and diseases. Finally, we review new advances in the treatment of PDAC, focusing on the discovery of novel drugs that directly inhibit KRAS and YAP function.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"44 1","pages":"6"},"PeriodicalIF":39.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1038/s41392-025-02534-y
Hayley M. Sabol, Lorenzo Galluzzi, Lucia Borriello
{"title":"Cell death: targeting ferroptosis in cancer","authors":"Hayley M. Sabol, Lorenzo Galluzzi, Lucia Borriello","doi":"10.1038/s41392-025-02534-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02534-y","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"359 1","pages":"5"},"PeriodicalIF":39.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1038/s41392-025-02328-2
Yu Liang, Wo-Ming Chen, Youming Zhang, Lei Li
Dormant tumor cells, major contributors to tumor recurrence and metastasis, are characterized by cell cycle arrest and reactivation potential. Tumor dormancy arises from the dynamic interplay between intrinsic tumor properties and extrinsic factors within the tumor ecosystem. This ecosystem operates at two distinct levels: the tumor microenvironment (TME) and the systemic macroenvironment (SME). Within the dormant TME, tumor cells engage in complex interactions with surrounding stromal cells, extracellular matrix components, and the vasculature, which are mediated through growth factors, cytokines, and metabolic byproducts. At the systemic level, the SME modulates tumor dormancy via inflammatory responses, metabolic homeostasis, hormonal regulation, and neural signaling. The TME and SME collectively maintain tumor dormancy through their bidirectional crosstalk. Disruption of this delicate ecological equilibrium can trigger tumor reactivation and metastatic progression. Consequently, effective therapeutic strategies should simultaneously target both TME remodeling and SME modulation. In this review, we provide a comprehensive analysis of the coordinated roles of the TME and SME in regulating tumor cell dormancy and reactivation while summarizing potential therapeutic approaches and clinical trials aimed at either eliminating dormant tumor cells or sustaining dormancy. Consequently, we propose a novel two-dimensional combined treatment strategy that concurrently addresses both the TME and SME to prevent tumor recurrence and metastasis.
{"title":"Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis","authors":"Yu Liang, Wo-Ming Chen, Youming Zhang, Lei Li","doi":"10.1038/s41392-025-02328-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02328-2","url":null,"abstract":"Dormant tumor cells, major contributors to tumor recurrence and metastasis, are characterized by cell cycle arrest and reactivation potential. Tumor dormancy arises from the dynamic interplay between intrinsic tumor properties and extrinsic factors within the tumor ecosystem. This ecosystem operates at two distinct levels: the tumor microenvironment (TME) and the systemic macroenvironment (SME). Within the dormant TME, tumor cells engage in complex interactions with surrounding stromal cells, extracellular matrix components, and the vasculature, which are mediated through growth factors, cytokines, and metabolic byproducts. At the systemic level, the SME modulates tumor dormancy via inflammatory responses, metabolic homeostasis, hormonal regulation, and neural signaling. The TME and SME collectively maintain tumor dormancy through their bidirectional crosstalk. Disruption of this delicate ecological equilibrium can trigger tumor reactivation and metastatic progression. Consequently, effective therapeutic strategies should simultaneously target both TME remodeling and SME modulation. In this review, we provide a comprehensive analysis of the coordinated roles of the TME and SME in regulating tumor cell dormancy and reactivation while summarizing potential therapeutic approaches and clinical trials aimed at either eliminating dormant tumor cells or sustaining dormancy. Consequently, we propose a novel two-dimensional combined treatment strategy that concurrently addresses both the TME and SME to prevent tumor recurrence and metastasis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"88 1","pages":"1"},"PeriodicalIF":39.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1038/s41392-025-02342-4
Jin Yang, Shimeng Wang, Xin Li, Hongdan Xu, Tongxu Sun, Tao Hu, Jingjing Luo, Hongmei Zhou
Precancers, defined as normal-appearing or morphologically altered tissues with a risk of oncogenesis, exhibit various detectable manifestations across anatomical sites, including epithelial dysplasia, metaplasia, hyperplasia, and stromal fibrosis. Considering the prevailing assumption that most cancers arise from precancers, early intervention at the precancerous stage has immense potential to reduce cancer-related morbidity and mortality. However, the complex signaling networks governing precancer initiation and progression remain elusive, hampering the development of effective targeted interventions. This review synthesizes three critical dimensions of precancer biology: historical foundations tracing the conceptual evolution of precancer research over the past century; mechanisms underlying the multistep progression of precancer biology, encompassing epithelial and macro/microenvironmental remodeling; and signaling networks cataloging dysregulated pathways and their therapeutic potential. Over 10 signaling pathways, including the transforming growth factor-β (TGF-β), p53, Wnt, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, drive multistep malignant transformation. We further synthesize emerging evidence supporting microenvironmental dominance, proposing the novel “soil degeneration” hypothesis. This paradigm shift underscores the necessity for dual-window intervention in which early-phase microenvironmental normalization prevents the establishment of precancerous lesions and advanced-phase treatment concurrently addresses epithelial malignancy and stromal degeneration. This review bridges foundational molecular discoveries with translational clinical potential and advocates for precision intervention frameworks that extend from biomarker-guided risk assessment to synergistic remodeling of the precancer microenvironment, thereby redefining precancer intervention in the molecularly targeted era.
{"title":"Signaling pathways and targeted interventions for precancers","authors":"Jin Yang, Shimeng Wang, Xin Li, Hongdan Xu, Tongxu Sun, Tao Hu, Jingjing Luo, Hongmei Zhou","doi":"10.1038/s41392-025-02342-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02342-4","url":null,"abstract":"Precancers, defined as normal-appearing or morphologically altered tissues with a risk of oncogenesis, exhibit various detectable manifestations across anatomical sites, including epithelial dysplasia, metaplasia, hyperplasia, and stromal fibrosis. Considering the prevailing assumption that most cancers arise from precancers, early intervention at the precancerous stage has immense potential to reduce cancer-related morbidity and mortality. However, the complex signaling networks governing precancer initiation and progression remain elusive, hampering the development of effective targeted interventions. This review synthesizes three critical dimensions of precancer biology: historical foundations tracing the conceptual evolution of precancer research over the past century; mechanisms underlying the multistep progression of precancer biology, encompassing epithelial and macro/microenvironmental remodeling; and signaling networks cataloging dysregulated pathways and their therapeutic potential. Over 10 signaling pathways, including the transforming growth factor-β (TGF-β), p53, Wnt, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, drive multistep malignant transformation. We further synthesize emerging evidence supporting microenvironmental dominance, proposing the novel “soil degeneration” hypothesis. This paradigm shift underscores the necessity for dual-window intervention in which early-phase microenvironmental normalization prevents the establishment of precancerous lesions and advanced-phase treatment concurrently addresses epithelial malignancy and stromal degeneration. This review bridges foundational molecular discoveries with translational clinical potential and advocates for precision intervention frameworks that extend from biomarker-guided risk assessment to synergistic remodeling of the precancer microenvironment, thereby redefining precancer intervention in the molecularly targeted era.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The mammalian target of rapamycin (mTOR) pathway is a central regulator of cellular growth, metabolism, and homeostasis, integrating a wide array of intracellular and extracellular cues, including nutrient availability, growth factors, and cellular stress, to coordinate anabolic and catabolic processes such as protein, lipid, and nucleotide synthesis; autophagy; and proteasomal degradation. The dysregulation of this signaling hub has broad implications for health and disease. To commemorate the 50th anniversary of the discovery of rapamycin, we provide a comprehensive synthesis of five decades of mTOR research. This review traces the historical trajectory from the early characterization of the biological effects of rapamycin to the elucidation of its molecular target and downstream pathways. We integrate fundamental and emerging insights into the roles of mTOR across nearly all domains of cell biology and development, with a particular focus on the expanding landscape of therapeutic interventions targeting this pathway. Special emphasis is placed on the crosstalk between mTOR signaling and mitochondrial regulation, highlighting the mechanisms by which these two metabolic hubs co-regulate cellular adaptation, survival, and disease progression. The dynamic interplay between mTOR and mitochondrial networks governs key aspects of bioenergetics, redox balance, and cell fate decisions and is increasingly implicated in pathophysiological contexts ranging from cancer and aging to neurodegenerative and immune disorders.
{"title":"mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.","authors":"Hanxiao Zhang, Xia Xiao, Zhenrui Pan, Svetlana Dokudovskaya","doi":"10.1038/s41392-025-02493-4","DOIUrl":"10.1038/s41392-025-02493-4","url":null,"abstract":"<p><p>The mammalian target of rapamycin (mTOR) pathway is a central regulator of cellular growth, metabolism, and homeostasis, integrating a wide array of intracellular and extracellular cues, including nutrient availability, growth factors, and cellular stress, to coordinate anabolic and catabolic processes such as protein, lipid, and nucleotide synthesis; autophagy; and proteasomal degradation. The dysregulation of this signaling hub has broad implications for health and disease. To commemorate the 50th anniversary of the discovery of rapamycin, we provide a comprehensive synthesis of five decades of mTOR research. This review traces the historical trajectory from the early characterization of the biological effects of rapamycin to the elucidation of its molecular target and downstream pathways. We integrate fundamental and emerging insights into the roles of mTOR across nearly all domains of cell biology and development, with a particular focus on the expanding landscape of therapeutic interventions targeting this pathway. Special emphasis is placed on the crosstalk between mTOR signaling and mitochondrial regulation, highlighting the mechanisms by which these two metabolic hubs co-regulate cellular adaptation, survival, and disease progression. The dynamic interplay between mTOR and mitochondrial networks governs key aspects of bioenergetics, redox balance, and cell fate decisions and is increasingly implicated in pathophysiological contexts ranging from cancer and aging to neurodegenerative and immune disorders.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"428"},"PeriodicalIF":52.7,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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