Pub Date : 2026-01-10DOI: 10.1038/s41392-025-02558-4
Hyeon-Ji Kim, Cheolhee Jeong, Sang-Heon Lee, Seungchan An, Gyu Hwan Hyun, Ga Young Lim, Ju-Yeon Kim, Junhyeong Lee, Min-Jung Park, Sung Won Kwon, Won Kim, Minsoo Noh, Yong-Hyun Han, Mi-Ock Lee
Metabolic dysfunction-associated steatotic liver disease (MASLD) is steadily increasing with life-threatening complications, underscoring the need for new therapeutic targets. In this study, we identified a novel long noncoding RNA, Wee1-AS , which is transcribed from the antisense strand of the Wee1 gene locus. The expression of Wee1-AS was greater in hepatocytes, particularly in the region around the central vein, and it was induced in response to high-fat diet challenge. Adeno-associated virus-mediated overexpression of Wee1-AS in mice strongly suppressed the symptoms of MASLD, underscoring its pivotal roles. Mechanistically, Wee1-AS enhances mitochondrial fatty acid oxidation by activating the CDK1/CYCLIN B1 complex through two mechanisms. First, it suppressed the transcription of the Wee1 gene by preventing access to the transcriptional machinery. Second, Wee1-AS bound and stabilized the CYCLIN B1 protein by suppressing ubiquitin/proteasome-mediated degradation. Notably, treatment with the WEE1 inhibitor adavosertib ameliorated MASLD symptoms by improving mitochondrial function in the liver. Consistently, knockdown of Wee1-AS led to lipid accumulation and mitochondrial dysfunction, both of which were reversed by adavosertib treatment in hepatocytes, indicating a functional interplay between Wee1-AS and WEE1 in regulating fatty acid oxidation. Furthermore, we identified a human homolog, LNC106435.1 , which improved mitochondrial function, suggesting that the modulation of LNC106435.1 may have potential therapeutic implications for managing MASLD.
{"title":"LncRNA Wee1-AS coordinates oxidative fatty acid metabolism through the activation of mitochondrial CDK1/CYCLIN B1","authors":"Hyeon-Ji Kim, Cheolhee Jeong, Sang-Heon Lee, Seungchan An, Gyu Hwan Hyun, Ga Young Lim, Ju-Yeon Kim, Junhyeong Lee, Min-Jung Park, Sung Won Kwon, Won Kim, Minsoo Noh, Yong-Hyun Han, Mi-Ock Lee","doi":"10.1038/s41392-025-02558-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02558-4","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is steadily increasing with life-threatening complications, underscoring the need for new therapeutic targets. In this study, we identified a novel long noncoding RNA, <jats:italic>Wee1-AS</jats:italic> , which is transcribed from the antisense strand of the <jats:italic>Wee1</jats:italic> gene locus. The expression of <jats:italic>Wee1-AS</jats:italic> was greater in hepatocytes, particularly in the region around the central vein, and it was induced in response to high-fat diet challenge. Adeno-associated virus-mediated overexpression of <jats:italic>Wee1-AS</jats:italic> in mice strongly suppressed the symptoms of MASLD, underscoring its pivotal roles. Mechanistically, <jats:italic>Wee1-AS</jats:italic> enhances mitochondrial fatty acid oxidation by activating the CDK1/CYCLIN B1 complex through two mechanisms. First, it suppressed the transcription of the <jats:italic>Wee1</jats:italic> gene by preventing access to the transcriptional machinery. Second, <jats:italic>Wee1-AS</jats:italic> bound and stabilized the CYCLIN B1 protein by suppressing ubiquitin/proteasome-mediated degradation. Notably, treatment with the WEE1 inhibitor adavosertib ameliorated MASLD symptoms by improving mitochondrial function in the liver. Consistently, knockdown of <jats:italic>Wee1-AS</jats:italic> led to lipid accumulation and mitochondrial dysfunction, both of which were reversed by adavosertib treatment in hepatocytes, indicating a functional interplay between <jats:italic>Wee1-AS</jats:italic> and WEE1 in regulating fatty acid oxidation. Furthermore, we identified a human homolog, <jats:italic>LNC106435.1</jats:italic> , which improved mitochondrial function, suggesting that the modulation of <jats:italic>LNC106435.1</jats:italic> may have potential therapeutic implications for managing MASLD.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"26 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145938202","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 : 2026-01-06DOI: 10.1038/s41392-025-02329-1
Huiting Che, Yidan Gao, Yonghu Xu, Hui Xu, Roland Eils, Mei Tian
Organ cross-talk, also known as the organ axis or organ interaction network, plays a vital role in maintaining physiological homeostasis and responding to environmental stimuli. This review comprehensively integrates cutting-edge observations in organ communication research, with a particular focus on the brain, heart, and gut—the three core organs that garner the most attention in organ connection studies. The current state of organ interaction network research is clearly presented as a Sankey diagram. For brain-related connections, the interactions among the brain-gut, brain-liver, and brain-heart connections are thoroughly reviewed; for heart-related connections, the relationships among the heart–kidney, heart–lung, and heart–liver connections are explored in detail; and for gut-related connections, the interactions among the gut–liver, gut–kidney, and gut–lung connections are emphasized. Additional information on other prevalent organ connections is systematically organized in tables for intuitive presentation. Through the integration of profound insights into molecular mechanisms and biological functions, the complex signaling pathways regulating organ interactions in health and disease states have been systematically elucidated. In terms of therapeutic strategy development, numerous directions with potential application value are proposed on the basis of these research findings. Furthermore, this review meticulously discusses the diverse methods and advanced technologies employed in organ connection research, comprehensively highlighting the critical role of technological support in advancing this field. In the future, this review advocates the adoption of network-driven models, innovative diagnostic approaches, and personalized treatment strategies to offer new perspectives for addressing complex diseases from a systems biology standpoint.
{"title":"Organ cross-talk: molecular mechanisms, biological functions, and therapeutic interventions for diseases","authors":"Huiting Che, Yidan Gao, Yonghu Xu, Hui Xu, Roland Eils, Mei Tian","doi":"10.1038/s41392-025-02329-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02329-1","url":null,"abstract":"Organ cross-talk, also known as the organ axis or organ interaction network, plays a vital role in maintaining physiological homeostasis and responding to environmental stimuli. This review comprehensively integrates cutting-edge observations in organ communication research, with a particular focus on the brain, heart, and gut—the three core organs that garner the most attention in organ connection studies. The current state of organ interaction network research is clearly presented as a Sankey diagram. For brain-related connections, the interactions among the brain-gut, brain-liver, and brain-heart connections are thoroughly reviewed; for heart-related connections, the relationships among the heart–kidney, heart–lung, and heart–liver connections are explored in detail; and for gut-related connections, the interactions among the gut–liver, gut–kidney, and gut–lung connections are emphasized. Additional information on other prevalent organ connections is systematically organized in tables for intuitive presentation. Through the integration of profound insights into molecular mechanisms and biological functions, the complex signaling pathways regulating organ interactions in health and disease states have been systematically elucidated. In terms of therapeutic strategy development, numerous directions with potential application value are proposed on the basis of these research findings. Furthermore, this review meticulously discusses the diverse methods and advanced technologies employed in organ connection research, comprehensively highlighting the critical role of technological support in advancing this field. In the future, this review advocates the adoption of network-driven models, innovative diagnostic approaches, and personalized treatment strategies to offer new perspectives for addressing complex diseases from a systems biology standpoint.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"50 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902332","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 : 2026-01-05DOI: 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}
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