Oligodendrocyte precursor cells (OPCs) rapidly respond to neural injury, becoming activated to preserve myelin homeostasis and interacting with diverse cell types in the central nervous system (CNS). However, the molecular basis of OPC communication with the CNS immune system remains poorly understood. In Alzheimer’s disease (AD), microglia respond to amyloid pathology in a neuroprotective manner. Here, we found that Bmp4 produced by late-stage OPCs, termed committed oligodendrocyte precursors (COPs), acts as a critical signal shaping microglial neuroprotective programs in the context of amyloid pathology. OPC-specific genetic ablation of Bmp4 in 5xFAD mice suppressed microglial immune responses and exacerbated amyloid deposition. Single-cell RNA sequencing revealed that Bmp4 deficiency in COPs led to downregulation of disease-associated microglia (DAM) genes in the microglial cluster. Mechanistically, Bmp4-dependent Smad1/5/8 signaling directly regulated Trem2 expression in microglia. Replenishment of Bmp4-expressing COPs in 5xFAD mice enhanced Trem2⁺ DAM acquisition, promoting beneficial barrier formation around Aβ plaques. Similarly, intracerebroventricular (ICV) administration of Sox10 promoter-driven AAV-Bmp4 efficiently ameliorated AD progression. Collectively, these findings uncover an OPC–microglia crosstalk that governs immune surveillance in AD, highlighting COP-targeted enhancement of Bmp4 as a promising avenue for interventions aimed at reinforcing early neuroprotective responses.
{"title":"Oligodendrocyte precursor cells–microglia crosstalk via BMP4 drives microglial neuroprotective response and mitigates Alzheimer’s disease","authors":"Soonbong Baek, Jaemyung Jang, Seungeun Yeo, Hyun Jin Jung, Youngshik Choe","doi":"10.1038/s41392-026-02620-9","DOIUrl":"https://doi.org/10.1038/s41392-026-02620-9","url":null,"abstract":"Oligodendrocyte precursor cells (OPCs) rapidly respond to neural injury, becoming activated to preserve myelin homeostasis and interacting with diverse cell types in the central nervous system (CNS). However, the molecular basis of OPC communication with the CNS immune system remains poorly understood. In Alzheimer’s disease (AD), microglia respond to amyloid pathology in a neuroprotective manner. Here, we found that Bmp4 produced by late-stage OPCs, termed committed oligodendrocyte precursors (COPs), acts as a critical signal shaping microglial neuroprotective programs in the context of amyloid pathology. OPC-specific genetic ablation of Bmp4 in 5xFAD mice suppressed microglial immune responses and exacerbated amyloid deposition. Single-cell RNA sequencing revealed that Bmp4 deficiency in COPs led to downregulation of disease-associated microglia (DAM) genes in the microglial cluster. Mechanistically, Bmp4-dependent Smad1/5/8 signaling directly regulated Trem2 expression in microglia. Replenishment of Bmp4-expressing COPs in 5xFAD mice enhanced Trem2⁺ DAM acquisition, promoting beneficial barrier formation around Aβ plaques. Similarly, intracerebroventricular (ICV) administration of Sox10 promoter-driven AAV-Bmp4 efficiently ameliorated AD progression. Collectively, these findings uncover an OPC–microglia crosstalk that governs immune surveillance in AD, highlighting COP-targeted enhancement of Bmp4 as a promising avenue for interventions aimed at reinforcing early neuroprotective responses.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"96 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506082","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 : 2026-03-25DOI: 10.1038/s41392-026-02628-1
Christos P. Kotanidis, Charalambos Antoniades
{"title":"Arterial inflammation after myocardial infarction: regulating the immune system","authors":"Christos P. Kotanidis, Charalambos Antoniades","doi":"10.1038/s41392-026-02628-1","DOIUrl":"https://doi.org/10.1038/s41392-026-02628-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"95 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506719","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}
Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling—driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications—plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This moderate oxidative stress promotes tumorigenesis by inducing DNA damage, genomic instability, and aberrant activation of proliferative and survival pathways, while also contributing to resistance to conventional therapies. Paradoxically, excessive ROS accumulation can overwhelm antioxidant defenses, triggering oxidative stress-induced programmed cell death (PCD) mechanisms, including apoptosis, autophagy, and ferroptosis. Owing to its dual role—facilitating both tumor progression and suppression—ROS have emerged as compelling yet complex targets in cancer therapy. Therapeutic strategies aimed at modulating ROS homeostasis, such as enhancing ROS production, inhibiting antioxidant systems, or targeting downstream redox-regulated signaling nodes, hold promise for selectively eliminating cancer cells. Furthermore, integrating redox profiling or “redox signatures” into personalized medicine approaches may optimize therapeutic efficacy while minimizing off-target toxicity. In this review, we critically examine the Janus-faced role of ROS in carcinogenesis, dissect the molecular pathways regulated by ROS in tumor biology, and explore current advancements, limitations, and future directions in redox-based anticancer therapeutic approaches.
{"title":"Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications","authors":"Sharmin Akter, Rajesh Madhuvilakku, Anik Kumar Kar, Irin Sultana Nila, Pengda Liu, Hiroyuki Inuzuka, Wenyi Wei, Yonggeun Hong","doi":"10.1038/s41392-026-02583-x","DOIUrl":"https://doi.org/10.1038/s41392-026-02583-x","url":null,"abstract":"Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling—driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications—plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This moderate oxidative stress promotes tumorigenesis by inducing DNA damage, genomic instability, and aberrant activation of proliferative and survival pathways, while also contributing to resistance to conventional therapies. Paradoxically, excessive ROS accumulation can overwhelm antioxidant defenses, triggering oxidative stress-induced programmed cell death (PCD) mechanisms, including apoptosis, autophagy, and ferroptosis. Owing to its dual role—facilitating both tumor progression and suppression—ROS have emerged as compelling yet complex targets in cancer therapy. Therapeutic strategies aimed at modulating ROS homeostasis, such as enhancing ROS production, inhibiting antioxidant systems, or targeting downstream redox-regulated signaling nodes, hold promise for selectively eliminating cancer cells. Furthermore, integrating redox profiling or “redox signatures” into personalized medicine approaches may optimize therapeutic efficacy while minimizing off-target toxicity. In this review, we critically examine the Janus-faced role of ROS in carcinogenesis, dissect the molecular pathways regulated by ROS in tumor biology, and explore current advancements, limitations, and future directions in redox-based anticancer therapeutic approaches.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506720","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}
Transforming growth factor beta (TGFβ) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression by promoting immune suppression, fibrosis, and metastasis. Given its central role in shaping the tumor microenvironment, TGFβ has attracted significant clinical interest as a target for immunotherapy. One promising and innovative approach involves TGFβ-based immune-modulatory vaccines (IMVs). In this study, we explored the immunogenic potential of multiple TGFβ-derived epitopes and assessed the clinical relevance of TGFβ-specific T cells in PDAC patients. We identified T cell responses towards multiple epitopes, TGFβ‑15, TGFβ‑33, and TGFβ‑38, in both healthy donors and PDAC patients, with TGFβ‑33 eliciting particularly robust responses in the patient cohort. These primarily CD4⁺ T cells displayed proinflammatory, as well as notable cytotoxic, properties and recognized target cells in a TGFβ-dependent manner. Moreover, we found that higher baseline frequencies of TGFβ‑33-specific T cells correlated with improved clinical outcomes following combined immune checkpoint inhibitor therapy and radiotherapy. Interestingly, patients with baseline responses to multiple TGFβ-derived epitopes had longer overall and progression-free survival compared to those with responses to none or a single epitope. Using a single mRNA construct encoding multiple TGFβ epitopes, we demonstrated effective activation of T cells specific for distinct TGFβ epitopes. These findings support the potential of a multi-epitope TGFβ-derived immune-modulatory vaccine to enhance anti-tumor immunity, representing a promising strategy to improve therapeutic responses in PDAC.
{"title":"Rationale for multi-epitope TGFβ vaccination in pancreatic cancer: evidence from immunologic and clinical correlates","authors":"Josephine Hallundbæk Ruders, Shamaila Munir Ahmad, Rasmus Erik Johansson Mortensen, Özcan Met, Mikkel Byrdal, Inna Markovna Chen, Susann Theile, Morten Orebo Holmström, Mads Hald Andersen","doi":"10.1038/s41392-026-02626-3","DOIUrl":"https://doi.org/10.1038/s41392-026-02626-3","url":null,"abstract":"Transforming growth factor beta (TGFβ) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression by promoting immune suppression, fibrosis, and metastasis. Given its central role in shaping the tumor microenvironment, TGFβ has attracted significant clinical interest as a target for immunotherapy. One promising and innovative approach involves TGFβ-based immune-modulatory vaccines (IMVs). In this study, we explored the immunogenic potential of multiple TGFβ-derived epitopes and assessed the clinical relevance of TGFβ-specific T cells in PDAC patients. We identified T cell responses towards multiple epitopes, TGFβ‑15, TGFβ‑33, and TGFβ‑38, in both healthy donors and PDAC patients, with TGFβ‑33 eliciting particularly robust responses in the patient cohort. These primarily CD4⁺ T cells displayed proinflammatory, as well as notable cytotoxic, properties and recognized target cells in a TGFβ-dependent manner. Moreover, we found that higher baseline frequencies of TGFβ‑33-specific T cells correlated with improved clinical outcomes following combined immune checkpoint inhibitor therapy and radiotherapy. Interestingly, patients with baseline responses to multiple TGFβ-derived epitopes had longer overall and progression-free survival compared to those with responses to none or a single epitope. Using a single mRNA construct encoding multiple TGFβ epitopes, we demonstrated effective activation of T cells specific for distinct TGFβ epitopes. These findings support the potential of a multi-epitope TGFβ-derived immune-modulatory vaccine to enhance anti-tumor immunity, representing a promising strategy to improve therapeutic responses in PDAC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"33 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496769","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 : 2026-03-23DOI: 10.1038/s41392-026-02637-0
Jiang Wang, Hanlin Wang, Runhua Du, Chunpu Li, Mingbo Su, Shuni Wang, Weijuan Kan, Guobin Liu, Yu Zhang, Xiaobei Hu, Feng Gao, Gaoya Xu, Cong Li, Wei Zhu, Yunfei Ye, Li Sheng, Yuqiang Shi, Yingying Shao, Jiangzhou Song, Yuxian Wang, Bo Wang, Yubo Zhou, He Huang, Jia Li, Hong Liu
Epigenetic dysregulation is a fundamental cancer hallmark, and lysine demethylase 1 (LSD1) is a central target for cancer intervention. Developing novel LSD1 inhibitors with high selectivity, favorable bioavailability, and safety for acute myeloid leukemia (AML) remains challenging. We developed DC551040, a highly potent, selective irreversible LSD1 inhibitor with good tolerability in Phase I AML clinical trial (CTR20222026). DC551040-LSD1 complex crystal structure uncovered a new binding pocket, providing molecular insights for subsequent LSD1 inhibitor design. Given the significant role of LSD1 in epigenetic regulation, we performed comprehensive transcriptomic and proteomic analyses to investigate gene and protein expression dynamics following DC551040 treatment in an MV-4-11 xenograft model. These analyses revealed that multiple immune and inflammation related pathways are activated upon DC551040 treatment, including the key members STAT5, NF-κB, and AKT, suggesting the potential for adaptive resistance. Through a search of the Connectivity Map (CMAP) database, we identify homoharringtonine (HHT), an approved anti-leukemia drug, which mimics the anti-transcriptional activation of inflammatory pathways. Subsequent in vitro and in vivo experiments validated the efficacy of combining HHT with DC551040, demonstrating a synergistic antitumor effect and extended survival in MV-4-11 disseminated xenograft model mice. Together, this study not only introduces a novel LSD1 inhibitor but also delves into the molecular mechanisms underlying LSD1 inhibitors, while proposing a promising combination therapy for AML individuals in clinical trials.
{"title":"Potent and selective LSD1 inhibitor DC551040 reveals a promising combination therapy for AML with insight into epigenetic dysregulation","authors":"Jiang Wang, Hanlin Wang, Runhua Du, Chunpu Li, Mingbo Su, Shuni Wang, Weijuan Kan, Guobin Liu, Yu Zhang, Xiaobei Hu, Feng Gao, Gaoya Xu, Cong Li, Wei Zhu, Yunfei Ye, Li Sheng, Yuqiang Shi, Yingying Shao, Jiangzhou Song, Yuxian Wang, Bo Wang, Yubo Zhou, He Huang, Jia Li, Hong Liu","doi":"10.1038/s41392-026-02637-0","DOIUrl":"https://doi.org/10.1038/s41392-026-02637-0","url":null,"abstract":"Epigenetic dysregulation is a fundamental cancer hallmark, and lysine demethylase 1 (LSD1) is a central target for cancer intervention. Developing novel LSD1 inhibitors with high selectivity, favorable bioavailability, and safety for acute myeloid leukemia (AML) remains challenging. We developed DC551040, a highly potent, selective irreversible LSD1 inhibitor with good tolerability in Phase I AML clinical trial (CTR20222026). DC551040-LSD1 complex crystal structure uncovered a new binding pocket, providing molecular insights for subsequent LSD1 inhibitor design. Given the significant role of LSD1 in epigenetic regulation, we performed comprehensive transcriptomic and proteomic analyses to investigate gene and protein expression dynamics following DC551040 treatment in an MV-4-11 xenograft model. These analyses revealed that multiple immune and inflammation related pathways are activated upon DC551040 treatment, including the key members STAT5, NF-κB, and AKT, suggesting the potential for adaptive resistance. Through a search of the Connectivity Map (CMAP) database, we identify homoharringtonine (HHT), an approved anti-leukemia drug, which mimics the anti-transcriptional activation of inflammatory pathways. Subsequent in vitro and in vivo experiments validated the efficacy of combining HHT with DC551040, demonstrating a synergistic antitumor effect and extended survival in MV-4-11 disseminated xenograft model mice. Together, this study not only introduces a novel LSD1 inhibitor but also delves into the molecular mechanisms underlying LSD1 inhibitors, while proposing a promising combination therapy for AML individuals in clinical trials.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"28 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496766","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 : 2026-03-23DOI: 10.1038/s41392-026-02615-6
Ke Xiong, Guanghua Wang, Desheng Li, Beihua Shao, Zhiwen Chen, Qicheng Zou, Xinrui Zhang, Yanru Dong, Xuxia Zhao, Yixin Yuan, Hongtao Xu, Yi Liu, Dandan Liang, Li Wang, Bin Zhou, Nianguo Dong, Duanyang Xie, Yi-Han Chen
Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, is closely linked to disturbed intracellular Ca2+ homeostasis. Visinin-like protein 1 (VILIP-1), newly identified in cardiomyocytes, has been implicated in modulating Ca2+ signaling, yet its role in AF remains undefined. In this study, we integrated bulk RNA sequencing, single-cell transcriptomics, and electrophysiological profiling from human AF patients and rodent AF models to identify VILIP-1 as a key mediator of Ca2+ dysregulation in AF. VILIP-1 was significantly upregulated in atrial tissues from AF patients and in pacing-induced rat AF models, with enhanced membrane localization in cardiomyocytes. Atrial cardiomyocyte-specific overexpression of VILIP-1 led to pathological Ca2+ leakage, promoting delayed afterdepolarizations (DADs) and action potential duration (APD) alternans, which fostered AF substrate formation and increased arrhythmia susceptibility. Mechanistically, VILIP-1 augmented the surface abundance of sodium-calcium exchanger 1 (NCX-1) via a myristoylation-dependent trafficking mechanism, thereby disrupting Ca2+ handling and initiating AF. Pharmacologically, repaglinide and desloratadine, two FDA-approved drugs that identified to target VILIP-1 or its myristoylation, attenuated AF susceptibility by reducing NCX-1 surface expression and restoring intracellular Ca2+ homeostasis. Collectively, our findings define VILIP-1 as a critical upstream modulator of atrial Ca2+ homeostasis and establish it as a promising therapeutic target for AF, with efficacy validated in human and rodent models.
{"title":"Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models","authors":"Ke Xiong, Guanghua Wang, Desheng Li, Beihua Shao, Zhiwen Chen, Qicheng Zou, Xinrui Zhang, Yanru Dong, Xuxia Zhao, Yixin Yuan, Hongtao Xu, Yi Liu, Dandan Liang, Li Wang, Bin Zhou, Nianguo Dong, Duanyang Xie, Yi-Han Chen","doi":"10.1038/s41392-026-02615-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02615-6","url":null,"abstract":"Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, is closely linked to disturbed intracellular Ca2+ homeostasis. Visinin-like protein 1 (VILIP-1), newly identified in cardiomyocytes, has been implicated in modulating Ca2+ signaling, yet its role in AF remains undefined. In this study, we integrated bulk RNA sequencing, single-cell transcriptomics, and electrophysiological profiling from human AF patients and rodent AF models to identify VILIP-1 as a key mediator of Ca2+ dysregulation in AF. VILIP-1 was significantly upregulated in atrial tissues from AF patients and in pacing-induced rat AF models, with enhanced membrane localization in cardiomyocytes. Atrial cardiomyocyte-specific overexpression of VILIP-1 led to pathological Ca2+ leakage, promoting delayed afterdepolarizations (DADs) and action potential duration (APD) alternans, which fostered AF substrate formation and increased arrhythmia susceptibility. Mechanistically, VILIP-1 augmented the surface abundance of sodium-calcium exchanger 1 (NCX-1) via a myristoylation-dependent trafficking mechanism, thereby disrupting Ca2+ handling and initiating AF. Pharmacologically, repaglinide and desloratadine, two FDA-approved drugs that identified to target VILIP-1 or its myristoylation, attenuated AF susceptibility by reducing NCX-1 surface expression and restoring intracellular Ca2+ homeostasis. Collectively, our findings define VILIP-1 as a critical upstream modulator of atrial Ca2+ homeostasis and establish it as a promising therapeutic target for AF, with efficacy validated in human and rodent models.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"401 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496767","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}
Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: fibrinogen levels <2 g/L were significantly associated with increased mortality, whereas levels >4 g/L were significantly associated with reduced mortality. Notably, fibrinogen was undetectable in aortic samples from control individuals without AD but accumulated in the aortic media of both AD patients and model mice. Importantly, fibrinogen accumulation was more pronounced in mice with advanced but unruptured AD, suggesting its role in maintaining vascular stability. AAV8-mediated fibrinogen knockdown significantly exacerbated AD, whereas exogenous supplementation with fibrinogen alleviated AD in mice, as evidenced by changes in the survival rate, aortic dilation, AD incidence, elastic fiber degradation, and collagen accumulation. Mechanistically, fibrinogen inhibited Bmal1 signaling, preventing detrimental vascular smooth muscle cell (VSMC) phenotypic transformation and contractility impairment. Finally, exogenous supplementation with the optimal dose of fibrinogen mitigates the progression of AD in mice. This study identified fibrinogen as a key regulator of VSMC contractility and aortic structural integrity, highlighting its potential as a novel therapeutic target to delay AD progression and extend the window for elective surgery.
{"title":"Fibrinogen-Bmal1 signaling as a therapeutic target to limit aortic dissection by preserving VSMC contractility.","authors":"Xiaohan Zhong,Dongjie Li,Yuanfei Zhao,Lu Dai,Jinzhang Li,Zhiqi Ji,Bojing Zuo,Hongshan Liu,Haixia Huang,Wei Wang,Haiyang Li,Yuyong Liu,Ming Gong,Xinliang Ma,Wenjian Jiang,Meili Wang,Hongjia Zhang","doi":"10.1038/s41392-026-02610-x","DOIUrl":"https://doi.org/10.1038/s41392-026-02610-x","url":null,"abstract":"Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: fibrinogen levels <2 g/L were significantly associated with increased mortality, whereas levels >4 g/L were significantly associated with reduced mortality. Notably, fibrinogen was undetectable in aortic samples from control individuals without AD but accumulated in the aortic media of both AD patients and model mice. Importantly, fibrinogen accumulation was more pronounced in mice with advanced but unruptured AD, suggesting its role in maintaining vascular stability. AAV8-mediated fibrinogen knockdown significantly exacerbated AD, whereas exogenous supplementation with fibrinogen alleviated AD in mice, as evidenced by changes in the survival rate, aortic dilation, AD incidence, elastic fiber degradation, and collagen accumulation. Mechanistically, fibrinogen inhibited Bmal1 signaling, preventing detrimental vascular smooth muscle cell (VSMC) phenotypic transformation and contractility impairment. Finally, exogenous supplementation with the optimal dose of fibrinogen mitigates the progression of AD in mice. This study identified fibrinogen as a key regulator of VSMC contractility and aortic structural integrity, highlighting its potential as a novel therapeutic target to delay AD progression and extend the window for elective surgery.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"102 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483384","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}
SHR-A1811, an antibody‒drug conjugate consisting of the anti-HER2 antibody trastuzumab conjugated via a cleavable linker to a topoisomerase I inhibitor payload, demonstrated substantial antitumor activity in patients with heavily treated HER2-expressing or mutated advanced solid tumors. The main analysis was reported, and this is a long-term follow-up of the HORIZON-X trial (NCT04446260). This global, multicenter, first-in-human, phase 1 trial enrolled patients aged ≥ 18 years with unresectable, advanced, or metastatic HER2-expressing or mutated solid tumors refractory or intolerant to standard therapies across 38 hospitals. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every three weeks. The primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. From September 7, 2020, to June 4, 2024, 396 patients with a median of three prior treatment regimens (IQR 2-5) received SHR-A1811. As of March 12, 2025, the median follow-up was 17.1 months for HER2-positive breast cancer, 10.6 months for HER2-low expressing breast cancer, and 4.3 to 8.2 months in non-breast cancers. The safety profile remained consistent with that of previous reports. Grade 3 or higher treatment-related adverse events occurred in 261 patients (65.9%), and any grade interstitial lung disease was observed in 10 patients (2.5%). The median progression-free survival was 25.0 months (95% CI 17.2-33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2-13.8) for HER2-low expressing breast cancer, and 3.5 to 17.2 months for non-breast tumors. This final analysis further confirmed the long-term efficacy and favorable safety profile of SHR-A1811 among heavily prior-treated advanced solid tumors, reinforcing its potential as an effective HER2-targeted therapy.
SHR-A1811是一种抗体-药物偶联物，由抗her2抗体曲妥珠单抗通过可切割连接物偶联到拓扑异构酶I抑制剂有效载荷组成，在重度治疗的表达her2或突变的晚期实体瘤患者中显示出显著的抗肿瘤活性。报告了主要分析，这是对HORIZON-X试验（NCT04446260）的长期随访。这项全球性、多中心、首次人体i期临床试验招募了年龄≥18岁的不可切除、晚期或转移性her2表达或突变实体瘤患者，这些患者难治性或对标准治疗不耐受，来自38家医院。SHR-A1811以每三周1.0至8.0 mg/kg的剂量静脉注射。主要终点包括剂量限制性毒性、安全性和推荐的2期剂量。从2020年9月7日至2024年6月4日，396名患者接受了shrr - a1811治疗，其中中位数为三种先前治疗方案（IQR 2-5）。截至2025年3月12日，her2阳性乳腺癌的中位随访时间为17.1个月，her2低表达乳腺癌为10.6个月，非乳腺癌为4.3至8.2个月。安全概况与以前的报告保持一致。261名患者（65.9%）发生了3级或以上的治疗相关不良事件，10名患者（2.5%）出现了任何级别的间质性肺疾病。her2阳性乳腺癌的中位无进展生存期为25.0个月（95% CI 17.2-33.6）， her2低表达乳腺癌的中位无进展生存期为11.0个月（95% CI 8.2-13.8），非乳腺肿瘤的中位无进展生存期为3.5 - 17.2个月。这一最终分析进一步证实了SHR-A1811在重度既往治疗的晚期实体瘤中的长期疗效和良好的安全性，增强了其作为一种有效的her2靶向治疗的潜力。
{"title":"SHR-A1811, a novel HER2-targeting antibody-drug conjugate, in advanced solid tumors (HORIZON-X): a global phase 1 trial.","authors":"Herui Yao,Min Yan,Zhongsheng Tong,Xinhong Wu,Yongmei Yin,Min-Hee Ryu,John J Park,Shusuan Jiang,Jee Hyun Kim,Shouman Wang,Yahua Zhong,Mark Voskoboynik,Jian Zhang,Andreas Kaubisch,Caigang Liu,Yu Chen,Seock-Ah Im,Lingying Wu,Yingbin Liu,Vinod Ganju,Minal Barve,Hui Li,Guangyu Yao,Mudan Yang,Lequn Bao,Yiming Zhao,Jianli Zhao,Kaijing Zhao,Yu Shen,Shangyi Rong,Xiaoyu Zhu,Erwei Song","doi":"10.1038/s41392-026-02612-9","DOIUrl":"https://doi.org/10.1038/s41392-026-02612-9","url":null,"abstract":"SHR-A1811, an antibody‒drug conjugate consisting of the anti-HER2 antibody trastuzumab conjugated via a cleavable linker to a topoisomerase I inhibitor payload, demonstrated substantial antitumor activity in patients with heavily treated HER2-expressing or mutated advanced solid tumors. The main analysis was reported, and this is a long-term follow-up of the HORIZON-X trial (NCT04446260). This global, multicenter, first-in-human, phase 1 trial enrolled patients aged ≥ 18 years with unresectable, advanced, or metastatic HER2-expressing or mutated solid tumors refractory or intolerant to standard therapies across 38 hospitals. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg every three weeks. The primary endpoints included dose-limiting toxicity, safety, and the recommended phase 2 dose. From September 7, 2020, to June 4, 2024, 396 patients with a median of three prior treatment regimens (IQR 2-5) received SHR-A1811. As of March 12, 2025, the median follow-up was 17.1 months for HER2-positive breast cancer, 10.6 months for HER2-low expressing breast cancer, and 4.3 to 8.2 months in non-breast cancers. The safety profile remained consistent with that of previous reports. Grade 3 or higher treatment-related adverse events occurred in 261 patients (65.9%), and any grade interstitial lung disease was observed in 10 patients (2.5%). The median progression-free survival was 25.0 months (95% CI 17.2-33.6) for HER2-positive breast cancer, 11.0 months (95% CI 8.2-13.8) for HER2-low expressing breast cancer, and 3.5 to 17.2 months for non-breast tumors. This final analysis further confirmed the long-term efficacy and favorable safety profile of SHR-A1811 among heavily prior-treated advanced solid tumors, reinforcing its potential as an effective HER2-targeted therapy.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483385","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}
Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide. Despite multimodal therapeutic advances, long-term survival remains poor, underscoring the need to identify novel molecular drivers of disease aggressiveness. Hypertranscription is a genome-wide increase in total RNA output that has emerged as a hallmark of oncogenic transformation. However, the role of mRNA-specific hypertranscription in HNSCC and its underlying molecular drivers remain undefined. In the present study, we investigated the association between mRNA hypertranscription and malignant phenotypes in HNSCC. Single-cell transcriptomics data revealed that elevated mRNA hypertranscription was significantly associated with the activation of oncogenic pathways and poor clinical outcomes. Through transcription factor activity analysis, we identified the transcription factor Spi-1 Proto-Oncogene (SPI1) as a potential regulator of mRNA hypertranscription in HNSCC malignant cells. Loss- and gain-of-function experiments in HNSCC cell lines and xenograft models established that SPI1 drives cell proliferation, invasion, migration, and tumor growth in vitro and in vivo. Mechanistically, inducible SPI1 overexpression elevated nascent RNA synthesis as measured by EU incorporation, and integrative ChIP-seq/RNA-seq profiling identified direct genomic targets of SPI1 enriched in oncogenic transcriptional programs. Collectively, our findings show that SPI1-driven mRNA hypertranscription is important in HNSCC progression and provide novel insights into the transcriptional dysregulation underlying aggressive malignancies.
{"title":"Spi-1 proto-oncogene regulates mRNA hypertranscription and malignant progression in head and neck cancer.","authors":"Zheran Liu,Zijian Qin,Huilin Li,Lili Zhu,Ling He,Na Chen,Dan Zhu,Qinghong Liu,Lei Dai,Xingchen Peng","doi":"10.1038/s41392-026-02669-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02669-6","url":null,"abstract":"Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide. Despite multimodal therapeutic advances, long-term survival remains poor, underscoring the need to identify novel molecular drivers of disease aggressiveness. Hypertranscription is a genome-wide increase in total RNA output that has emerged as a hallmark of oncogenic transformation. However, the role of mRNA-specific hypertranscription in HNSCC and its underlying molecular drivers remain undefined. In the present study, we investigated the association between mRNA hypertranscription and malignant phenotypes in HNSCC. Single-cell transcriptomics data revealed that elevated mRNA hypertranscription was significantly associated with the activation of oncogenic pathways and poor clinical outcomes. Through transcription factor activity analysis, we identified the transcription factor Spi-1 Proto-Oncogene (SPI1) as a potential regulator of mRNA hypertranscription in HNSCC malignant cells. Loss- and gain-of-function experiments in HNSCC cell lines and xenograft models established that SPI1 drives cell proliferation, invasion, migration, and tumor growth in vitro and in vivo. Mechanistically, inducible SPI1 overexpression elevated nascent RNA synthesis as measured by EU incorporation, and integrative ChIP-seq/RNA-seq profiling identified direct genomic targets of SPI1 enriched in oncogenic transcriptional programs. Collectively, our findings show that SPI1-driven mRNA hypertranscription is important in HNSCC progression and provide novel insights into the transcriptional dysregulation underlying aggressive malignancies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"79 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478879","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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