Obesity exhibits a high heritability with heterogeneity; however, the genetic variants identified as obesity-causing factors are still underexplored. By performing deep sequencing on 2295 cases of young-onset obesity from East Asian populations and 2292 lean controls, we identified five genes ( TUB , NR4A3 , HIST1H4D , DXO , and TELO2 ) with an excess burden of rare predicted loss-of-function (LoF) variants in cases. Among the variants, TUB p.R364G was identified as a potential deleterious variant that disrupted TUB protein’s subcellular localization. Knock-in mice carrying the homologous p.R363G variant exhibited hyperphagia and obesity in an allele dose–dependent manner when fed a high-fat diet. The TUB p.R363G variant also blunted responses to leptin-induced suppression of food intake, leading to leptin resistance in mice. Furthermore, we demonstrated that TUB acted as a positive regulator of the leptin pathway through its interaction with STAT3, and this interaction was impaired by the p.R364G variant. TUB silencing mitigated the inhibitory effects of leptin on the activities of agouti-related protein (AgRP)–expressing neurons. Consistently, conditional ablation of TUB in AgRP + neurons in mice led to hyperphagic obesity and attenuated leptin-induced appetite suppression in mice. Thus, our study demonstrates that rare LoF variants in TUB predispose to young-onset obesity in humans, likely through impairing leptin sensitivity in AgRP + neurons.
{"title":"The TUB variant impairs leptin sensitivity and AgRP neuronal response, leading to obesity","authors":"Muye Tong, Yanru Chen, Beite Song, Jie Hong, Weiqiong Gu, Juan Shen, Huanjie Yang, Huimin Xia, Qian Li, Yufei Chen, Shaoqian Zhao, Qianqian Lyu, Wenzhi Xue, Qinyun Ma, Houde Zhou, Huixuan Wu, Yihua Guo, Zhiwen Cao, Yuxiao Zhao, Minchun Zhang, Xuejiang Gu, Jie Zheng, Yifei Zhang, Jieli Lu, Guang Ning, Yufang Bi, Weiqing Wang, Ruixin Liu, Jiqiu Wang","doi":"10.1126/scitranslmed.adw0458","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw0458","url":null,"abstract":"Obesity exhibits a high heritability with heterogeneity; however, the genetic variants identified as obesity-causing factors are still underexplored. By performing deep sequencing on 2295 cases of young-onset obesity from East Asian populations and 2292 lean controls, we identified five genes ( <jats:italic toggle=\"yes\">TUB</jats:italic> , <jats:italic toggle=\"yes\">NR4A3</jats:italic> , <jats:italic toggle=\"yes\">HIST1H4D</jats:italic> , <jats:italic toggle=\"yes\">DXO</jats:italic> , and <jats:italic toggle=\"yes\">TELO2</jats:italic> ) with an excess burden of rare predicted loss-of-function (LoF) variants in cases. Among the variants, TUB p.R364G was identified as a potential deleterious variant that disrupted TUB protein’s subcellular localization. Knock-in mice carrying the homologous p.R363G variant exhibited hyperphagia and obesity in an allele dose–dependent manner when fed a high-fat diet. The TUB p.R363G variant also blunted responses to leptin-induced suppression of food intake, leading to leptin resistance in mice. Furthermore, we demonstrated that TUB acted as a positive regulator of the leptin pathway through its interaction with STAT3, and this interaction was impaired by the p.R364G variant. TUB silencing mitigated the inhibitory effects of leptin on the activities of agouti-related protein (AgRP)–expressing neurons. Consistently, conditional ablation of TUB in AgRP <jats:sup>+</jats:sup> neurons in mice led to hyperphagic obesity and attenuated leptin-induced appetite suppression in mice. Thus, our study demonstrates that rare LoF variants in TUB predispose to young-onset obesity in humans, likely through impairing leptin sensitivity in AgRP <jats:sup>+</jats:sup> neurons.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"46 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153679","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 : 2026-02-11DOI: 10.1126/scitranslmed.ads6299
J. Christopher Hennings, Keerthana S. Murthy, Nicolas Picard, Inês Cabrita, David Böhm, Antje K. Huebner, Maria E. Krause, Gregor J. Gentsch, Vandit Shah, Jennifer Baraka-Vidot, Mukhran Khundadze, Diana Schmerler, Michael Kiehntopf, Tobias Stauber, Detlef Böckenhauer, Thomas J. Jentsch, Sebastian Bachmann, Christian Franke, Bernhard Schermer, Dominique Eladari, Régine Chambrey, Christian A. Hübner
Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low–molecular weight proteins, a condition also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on ATPase H + transporting V0 subunit a4 ( Atp6v0a4 ) knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that ras analog in brain 7 (Rab7), a key regulator of endolysosomal trafficking and lysosomal biogenesis, was diminished, and the number of abnormal lysosomal-associated membrane protein 1 (Lamp1)–positive vesicles labeled for increased sodium tolerance 1 (Ist1) was increased in proximal tubules of Atp6v0a4 KO mice. This was accompanied by the accumulation of autophagosomes, autolysosomes, and autophagic substrates. Correction of metabolic acidosis with bicarbonate therapy resolved proximal tubule dysfunction and trafficking defects in Atp6v0a4 KO mice. After 28 days of acid challenge, wild-type mice showed comparable trafficking defects to Rab7 down-regulation and an increase in Ist1-labeled Lamp1-positive vesicles and proximal tubule damage. Acidosis-induced decreases in RAB7-labeled particles and increased numbers of IST1-labeled LAMP1-positive particles also occurred in proximal tubule correlates of human kidney organoids derived from the widely used induced pluripotent stem cell line KOLF2.1J. Together, our data provide insight into why patients suffering from severe dRTA can develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.
患有远端肾小管酸中毒（dRTA）的患者有时被诊断为近端肾小管功能障碍，并伴有磷酸盐、尿酸、氨基酸和低分子量蛋白质的泄漏，这种情况也被称为fanconi样综合征。潜在的分子基础在很大程度上是难以捉摸的。我们之前报道了ATPase H +转运V0亚基a4 （Atp6v0a4）敲除（KO）小鼠，这些小鼠表现出严重的代谢性酸中毒，并伴有近端小管功能障碍，如磷酸尿和蛋白尿。在这里，我们发现在Atp6v0a4 KO小鼠的近端小管中，脑7 （Rab7）中的ras类似物（内溶酶体运输和溶酶体生物发生的关键调节因子）减少，并且标记为增加钠耐受性1 （Ist1）的异常溶酶体相关膜蛋白1 （Lamp1）阳性囊泡的数量增加。这伴随着自噬小体、自噬小体和自噬底物的积累。用碳酸氢盐治疗纠正代谢性酸中毒，解决了Atp6v0a4 KO小鼠近端小管功能障碍和运输缺陷。酸刺激28天后，野生型小鼠表现出与Rab7下调相似的运输缺陷，ist1标记的lamp1阳性囊泡和近端小管损伤增加。来源于广泛使用的诱导多能干细胞系KOLF2.1J的人肾类器官近端小管相关细胞中也出现酸中毒诱导的rab7标记颗粒减少和ist1标记的lamp1阳性颗粒数量增加。总之，我们的数据提供了为什么患有严重dRTA的患者可以发展为fanconi样综合征，这可能有助于慢性肾衰竭的进展。
{"title":"Metabolic acidosis causes a Fanconi-like syndrome with intracellular trafficking defects and proximal tubule dysfunction","authors":"J. Christopher Hennings, Keerthana S. Murthy, Nicolas Picard, Inês Cabrita, David Böhm, Antje K. Huebner, Maria E. Krause, Gregor J. Gentsch, Vandit Shah, Jennifer Baraka-Vidot, Mukhran Khundadze, Diana Schmerler, Michael Kiehntopf, Tobias Stauber, Detlef Böckenhauer, Thomas J. Jentsch, Sebastian Bachmann, Christian Franke, Bernhard Schermer, Dominique Eladari, Régine Chambrey, Christian A. Hübner","doi":"10.1126/scitranslmed.ads6299","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads6299","url":null,"abstract":"Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low–molecular weight proteins, a condition also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on ATPase H <jats:sup>+</jats:sup> transporting V0 subunit a4 ( <jats:italic toggle=\"yes\">Atp6v0a4</jats:italic> ) knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that ras analog in brain 7 (Rab7), a key regulator of endolysosomal trafficking and lysosomal biogenesis, was diminished, and the number of abnormal lysosomal-associated membrane protein 1 (Lamp1)–positive vesicles labeled for increased sodium tolerance 1 (Ist1) was increased in proximal tubules of <jats:italic toggle=\"yes\">Atp6v0a4</jats:italic> KO mice. This was accompanied by the accumulation of autophagosomes, autolysosomes, and autophagic substrates. Correction of metabolic acidosis with bicarbonate therapy resolved proximal tubule dysfunction and trafficking defects in <jats:italic toggle=\"yes\">Atp6v0a4</jats:italic> KO mice. After 28 days of acid challenge, wild-type mice showed comparable trafficking defects to Rab7 down-regulation and an increase in Ist1-labeled Lamp1-positive vesicles and proximal tubule damage. Acidosis-induced decreases in RAB7-labeled particles and increased numbers of IST1-labeled LAMP1-positive particles also occurred in proximal tubule correlates of human kidney organoids derived from the widely used induced pluripotent stem cell line KOLF2.1J. Together, our data provide insight into why patients suffering from severe dRTA can develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"6 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153678","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}
Gastrointestinal viruses such as rotavirus remain a major cause of childhood gastroenteritis and mortality worldwide. Although current live-attenuated rotavirus vaccines are effective, they face challenges including production, reduced efficacy in low- and middle-income countries, and rare adverse events, highlighting the need for vaccines that can induce strong gut mucosal immunity. Here, we introduce a lipid nanoparticle (LNP) platform that codelivers messenger RNA (mRNA) and the retinoic acid receptor agonist Am80 (Am80-LNP), enabling antigen-specific mucosal immune responses in the gut via parenteral intramuscular vaccination. Am80 incorporation preserved the vaccine’s ability to imprint expression of the gut-homing receptors CCR9 and α4β7 on T and B cells, improved mRNA delivery, enhanced lymph node accumulation, and mitigated injection-site inflammation driven by the LNP. In mice and Bama miniature pigs, Am80-LNP induced antigen-specific serum antibody titers, cellular immune responses, and intestinal IgA production. Neonatal mice vaccinated with Am80-LNP exhibited reduced incidence and duration of diarrhea after live rotavirus challenge, whereas LNPs without Am80 conferred negligible protection. These findings highlight the importance of gut mucosal immunity in mediating protection against rotavirus and suggest that Am80-LNP may offer a versatile mRNA vaccine platform against gastrointestinal viruses.
{"title":"Parenteral vaccination with an adjuvanted mRNA vaccine induces protective mucosal immunity against rotavirus in neonatal mice","authors":"Jingjiao Li, Yu Liu, Xinghuan Ma, Sujia Liu, Chen Yang, Yuzhou Zhang, Xingdi Cheng, Yixing Wen, Shiwei Mi, Haowei Zu, Wei Li, Yuanyuan Zhao, Qing Li, Shuai Liu, Haonan Huo, Guizhi Shi, Jiaqi Lin, Xueguang Lu","doi":"10.1126/scitranslmed.adw6105","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw6105","url":null,"abstract":"Gastrointestinal viruses such as rotavirus remain a major cause of childhood gastroenteritis and mortality worldwide. Although current live-attenuated rotavirus vaccines are effective, they face challenges including production, reduced efficacy in low- and middle-income countries, and rare adverse events, highlighting the need for vaccines that can induce strong gut mucosal immunity. Here, we introduce a lipid nanoparticle (LNP) platform that codelivers messenger RNA (mRNA) and the retinoic acid receptor agonist Am80 (Am80-LNP), enabling antigen-specific mucosal immune responses in the gut via parenteral intramuscular vaccination. Am80 incorporation preserved the vaccine’s ability to imprint expression of the gut-homing receptors CCR9 and α4β7 on T and B cells, improved mRNA delivery, enhanced lymph node accumulation, and mitigated injection-site inflammation driven by the LNP. In mice and Bama miniature pigs, Am80-LNP induced antigen-specific serum antibody titers, cellular immune responses, and intestinal IgA production. Neonatal mice vaccinated with Am80-LNP exhibited reduced incidence and duration of diarrhea after live rotavirus challenge, whereas LNPs without Am80 conferred negligible protection. These findings highlight the importance of gut mucosal immunity in mediating protection against rotavirus and suggest that Am80-LNP may offer a versatile mRNA vaccine platform against gastrointestinal viruses.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"46 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153567","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 : 2026-02-11DOI: 10.1126/scitranslmed.adp3984
Nalini R. Rao, Ivan Santiago-Marrero, Olivia DeGulis, Toshihiro Nomura, Kritika Goyal, SeungEun Lee, Timothy J. Hark, Justin C. Dynes, Emily X. Dexter, Maciej Dulewicz, Junyue Ge, Arun Upadhyay, Eugenio F. Fornasiero, Robert Vassar, Jörg Hanrieder, Anis Contractor, Jeffrey N. Savas
Amyloid-β (Aβ) peptides are a defining feature of Alzheimer’s disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ 42 in the SV lumen. Levetiracetam (Lev) is a US Food and Drug Administration–approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ 42 levels by reducing amyloidogenic APP processing in an SV2a-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway. Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ 42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Last, early Aβ pathology in brains from donors with Down syndrome was characterized by elevated presynaptic proteins. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.
淀粉样蛋白-β (a β)肽是阿尔茨海默病（AD）的一个决定性特征。这些肽是由淀粉样前体蛋白（APP）的蛋白水解加工产生的，这可以通过突触囊泡（SV）循环发生。然而，淀粉样变性APP加工如何改变SV组成和突触前功能尚不清楚。通过App敲入小鼠淀粉样蛋白病理模型，我们发现降解受损的蛋白与SV管腔中的Aβ 42一起积聚在突触前位点。左乙拉西坦（Lev）是美国食品和药物管理局批准的一种针对SVs的抗癫痫药物，并已显示出通过一种未明确的机制减少AD表型的治疗潜力。我们发现Lev通过以sv2a依赖的方式减少淀粉样变性APP加工来降低Aβ 42水平。Lev修饰SV循环，增加APP细胞表面表达，促进其通过非淀粉样变性途径优先加工。稳定同位素标记结合质谱法证实Lev可阻止体内产生Aβ 42。在具有侵袭性淀粉样蛋白病理的转基因小鼠中，电生理学和免疫荧光证实Lev可恢复SV循环异常并减少突触损失。最后，唐氏综合征供体的早期Aβ病理表现为突触前蛋白升高。总之，这些发现强调了在不可逆损伤发生之前预防Aβ病理的潜力。
{"title":"Levetiracetam prevents Aβ production through SV2a-dependent modulation of APP processing in Alzheimer’s disease models","authors":"Nalini R. Rao, Ivan Santiago-Marrero, Olivia DeGulis, Toshihiro Nomura, Kritika Goyal, SeungEun Lee, Timothy J. Hark, Justin C. Dynes, Emily X. Dexter, Maciej Dulewicz, Junyue Ge, Arun Upadhyay, Eugenio F. Fornasiero, Robert Vassar, Jörg Hanrieder, Anis Contractor, Jeffrey N. Savas","doi":"10.1126/scitranslmed.adp3984","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp3984","url":null,"abstract":"Amyloid-β (Aβ) peptides are a defining feature of Alzheimer’s disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ <jats:sub>42</jats:sub> in the SV lumen. Levetiracetam (Lev) is a US Food and Drug Administration–approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ <jats:sub>42</jats:sub> levels by reducing amyloidogenic APP processing in an SV2a-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway. Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ <jats:sub>42</jats:sub> production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Last, early Aβ pathology in brains from donors with Down syndrome was characterized by elevated presynaptic proteins. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"32 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153350","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 : 2026-02-11DOI: 10.1126/scitranslmed.adw5223
Mitchell J. Cohen, Christopher B. Erickson, Ian S. Lacroix, Margot Debot, Monika Dzieciatkowska, Sanchayita Sen, Terry R. Schaid, Lauren T. Gallagher, William M. Hallas, Otto N. Thielen, Alexis L. Cralley, Benjamin W. Stocker, Benjamin J. Ramser, Ava Mokhtari, Huma Baig, Christopher Sublette, Franklyn Iheagwam, Alyssa Caldwell-McGee, Jamie Cole, Kelly Nash, Marissa Pokharel, Jessica C. Cardenas, Anirban Banerjee, Ernest E. Moore, Christopher C. Silliman, Alan Hubbard, Angelo D’Alessandro, Kirk C. Hansen
Understanding the complexity of trauma-induced thromboinflammation necessitates data-driven approaches. We hypothesized that longitudinal plasma profiling could reveal underlying differences in patients with injury who present with similar clinical characteristics but ultimately have different outcomes. Here, we performed multiomic analyses of longitudinal plasma samples from a clinical trial of patients with traumatic injury to identify molecular endotypes and trajectories that were associated with patient outcomes. The pathophysiologic states of patients with trauma were defined by the longitudinal proteomic and metabolomic plasma profiles from a diverse cohort. Then, patients were endotyped according to their longitudinal trajectories through trauma omic states, and injury patterns and outcomes were compared. We identified endotypes associated with divergent clinical outcomes despite similar injury patterns at presentation. Organ failure and time spent in the intensive care unit (ICU) were predicted with high accuracy using omic markers. Patients who presented with evidence of elevated proteasome activation, catabolism, and superoxide formation were vulnerable to heart failure, lung failure, and acute lung injury, respectively. In addition, omic markers of increased hypoxia, RBC lysis, and hydrolase activity better fit mortality and ICU time compared with injury covariates, while providing biological insight. Injury and outcome patterns persisted in a validation trauma cohort after endotype assignment at a single, early time point. These data align with the understanding that patients with trauma may experience markedly different biological responses and outcomes despite similar clinical presentations. We suggest that mapping patient trajectories through biological injury states could provide a framework for personalized patient treatment after trauma.
{"title":"Multiomic analyses of longitudinal plasma samples identify thromboinflammation endotypes and trajectories in patients with trauma","authors":"Mitchell J. Cohen, Christopher B. Erickson, Ian S. Lacroix, Margot Debot, Monika Dzieciatkowska, Sanchayita Sen, Terry R. Schaid, Lauren T. Gallagher, William M. Hallas, Otto N. Thielen, Alexis L. Cralley, Benjamin W. Stocker, Benjamin J. Ramser, Ava Mokhtari, Huma Baig, Christopher Sublette, Franklyn Iheagwam, Alyssa Caldwell-McGee, Jamie Cole, Kelly Nash, Marissa Pokharel, Jessica C. Cardenas, Anirban Banerjee, Ernest E. Moore, Christopher C. Silliman, Alan Hubbard, Angelo D’Alessandro, Kirk C. Hansen","doi":"10.1126/scitranslmed.adw5223","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw5223","url":null,"abstract":"Understanding the complexity of trauma-induced thromboinflammation necessitates data-driven approaches. We hypothesized that longitudinal plasma profiling could reveal underlying differences in patients with injury who present with similar clinical characteristics but ultimately have different outcomes. Here, we performed multiomic analyses of longitudinal plasma samples from a clinical trial of patients with traumatic injury to identify molecular endotypes and trajectories that were associated with patient outcomes. The pathophysiologic states of patients with trauma were defined by the longitudinal proteomic and metabolomic plasma profiles from a diverse cohort. Then, patients were endotyped according to their longitudinal trajectories through trauma omic states, and injury patterns and outcomes were compared. We identified endotypes associated with divergent clinical outcomes despite similar injury patterns at presentation. Organ failure and time spent in the intensive care unit (ICU) were predicted with high accuracy using omic markers. Patients who presented with evidence of elevated proteasome activation, catabolism, and superoxide formation were vulnerable to heart failure, lung failure, and acute lung injury, respectively. In addition, omic markers of increased hypoxia, RBC lysis, and hydrolase activity better fit mortality and ICU time compared with injury covariates, while providing biological insight. Injury and outcome patterns persisted in a validation trauma cohort after endotype assignment at a single, early time point. These data align with the understanding that patients with trauma may experience markedly different biological responses and outcomes despite similar clinical presentations. We suggest that mapping patient trajectories through biological injury states could provide a framework for personalized patient treatment after trauma.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153351","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 : 2026-02-11DOI: 10.1126/scitranslmed.adw0834
Georgios Batsios, Céline Taglang, Suresh Udutha, Anne Marie Gillespie, Timothy Phoenix, Sabine Mueller, Sriram Venneti, Carl Koschmann, Pavithra Viswanath
Hyperactivation of glucose metabolism to lactate is a metabolic hallmark of cancer. However, the functional role of lactate in pediatric diffuse midline glioma (DMG) cells is unclear. Here, using stable isotope tracing and loss-of-function studies in clinically relevant patient-derived DMG models, we show that the oncogenic histone H3K27M mutation epigenetically up-regulates the rate-limiting glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U- 13 C]-glucose in DMGs. Mechanistically, lactate posttranslationally activates the nucleoside diphosphate kinase NME1 through lactylation and facilitates the synthesis of nucleoside triphosphates that are essential for DNA replication and tumor proliferation. This mechanistic link between glycolysis and nucleotide biosynthesis provides the opportunity for deuterium metabolic imaging of tumor growth and response to therapy. Spatially mapping 2 H-lactate production from [6,6- 2 H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard of care and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations in tumor tissues in preclinical DMG models in vivo at clinical field strength (3 T). Overall, we have identified an H3K27M-lactate-NME1 axis that drives DMG proliferation and facilitates noninvasive in vivo metabolic imaging of DMGs.
{"title":"Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in preclinical models of H3K27M-mutant gliomas","authors":"Georgios Batsios, Céline Taglang, Suresh Udutha, Anne Marie Gillespie, Timothy Phoenix, Sabine Mueller, Sriram Venneti, Carl Koschmann, Pavithra Viswanath","doi":"10.1126/scitranslmed.adw0834","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw0834","url":null,"abstract":"Hyperactivation of glucose metabolism to lactate is a metabolic hallmark of cancer. However, the functional role of lactate in pediatric diffuse midline glioma (DMG) cells is unclear. Here, using stable isotope tracing and loss-of-function studies in clinically relevant patient-derived DMG models, we show that the oncogenic histone H3K27M mutation epigenetically up-regulates the rate-limiting glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U- <jats:sup>13</jats:sup> C]-glucose in DMGs. Mechanistically, lactate posttranslationally activates the nucleoside diphosphate kinase NME1 through lactylation and facilitates the synthesis of nucleoside triphosphates that are essential for DNA replication and tumor proliferation. This mechanistic link between glycolysis and nucleotide biosynthesis provides the opportunity for deuterium metabolic imaging of tumor growth and response to therapy. Spatially mapping <jats:sup>2</jats:sup> H-lactate production from [6,6- <jats:sup>2</jats:sup> H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard of care and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations in tumor tissues in preclinical DMG models in vivo at clinical field strength (3 T). Overall, we have identified an H3K27M-lactate-NME1 axis that drives DMG proliferation and facilitates noninvasive in vivo metabolic imaging of DMGs.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"9 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153566","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 : 2026-02-04DOI: 10.1126/scitranslmed.ado6222
Jonas A. Kengne-Ouafo, Mersimine F. M. Kouamo, Abdullahi Muhammad, Arnaud Tepa, Stevia Ntadoun, Leon M. J. Mugenzi, Theofelix Tekoh, Jack Hearn, Magellan Tchouakui, Murielle Wondji, Sulaiman S. Ibrahim, Charles S. Wondji
Deciphering the molecular drivers of insecticide resistance is paramount to extending the effectiveness of malaria vector control tools. Here, we demonstrate that a P450 haplotype spanning a Glu205→Asp (E205D) amino acid point mutation in the CYP6P3 gene drives pyrethroid insecticide resistance in the mosquito malaria vector Anopheles gambiae. Pooled whole-genome DNA sequencing data from A. gambiae mosquitoes detected a major P450-linked locus (CYP6 haplotype) on chromosome 2R adjacent to the locus encoding a sodium channel. In vitro metabolism assays with recombinantly expressed CYP6P3 protein revealed that the catalytic efficiency of the 205D variant for the pyrethroid insecticide permethrin was 3.7 times higher than that of the E205 variant. Similar findings were made for the related insecticide α-cypermethrin. Overexpression of the 205D variant in transgenic flies conferred higher resistance to pyrethroids compared with flies expressing the susceptible E205 variant. A DNA-based assay confirmed that the CYP6P3-E205D variant correlates with pyrethroid resistance in field mosquito populations [odds ratio (OR): 26.4; P < 0.0001] and reduces the efficacy of pyrethroid-only long-lasting insecticide bed nets. The homozygous resistance genotype of A. gambiae exhibited higher survival after exposure to the PermaNet 3.0 bed net compared with the susceptible SS genotype (OR: 6.1; P = 0.011). Furthermore, the CYP6P3-E205D variant together with the kdr target-site resistance mechanism exacerbated the loss of bed net efficacy. The 205D variant is predominant in West and Central Africa but less abundant or absent in East and South Africa, with signs of introgression with Anopheles coluzzii in Ghana.
破译杀虫剂抗性的分子驱动因素对于扩大疟疾病媒控制工具的有效性至关重要。在此，我们证明了P450单倍型在CYP6P3基因中跨越Glu205→Asp （E205D）氨基酸点突变驱动疟疾媒介冈比亚按蚊对拟除虫菊酯杀虫剂的抗性。冈比亚按蚊全基因组DNA测序数据在2R染色体上发现了一个主要的p450连锁位点（CYP6单倍型），与编码钠通道的位点相邻。重组表达的CYP6P3蛋白体外代谢实验表明，205D突变体对拟除虫菊酯类杀虫剂氯菊酯的催化效率是E205突变体的3.7倍。相关杀虫剂α-氯氰菊酯也有类似的结果。与表达易感基因E205变体的果蝇相比，转基因果蝇中过表达205D变体对拟除虫菊酯具有更高的抗性。一项基于dna的分析证实CYP6P3-E205D变异与野外蚊子种群对拟除虫菊酯类杀虫剂的抗性相关[优势比（OR）： 26.4；P <； 0.0001]并降低了只使用拟除虫菊酯的长效杀虫剂蚊帐的功效。纯合子抗性基因型冈比亚疟蚊暴露于PermaNet 3.0蚊帐后的存活率高于敏感基因型（OR: 6.1; P = 0.011）。此外，CYP6P3-E205D变异与kdr靶位耐药机制一起加剧了蚊帐功效的丧失。205D变体在西非和中非占主导地位，但在东非和南非数量较少或不存在，在加纳有与科鲁兹按蚊渗入的迹象。
{"title":"The E205D mutation in CYP6P3 drives pyrethroid insecticide resistance in the African malaria mosquito vector Anopheles gambiae","authors":"Jonas A. Kengne-Ouafo, Mersimine F. M. Kouamo, Abdullahi Muhammad, Arnaud Tepa, Stevia Ntadoun, Leon M. J. Mugenzi, Theofelix Tekoh, Jack Hearn, Magellan Tchouakui, Murielle Wondji, Sulaiman S. Ibrahim, Charles S. Wondji","doi":"10.1126/scitranslmed.ado6222","DOIUrl":"10.1126/scitranslmed.ado6222","url":null,"abstract":"<div >Deciphering the molecular drivers of insecticide resistance is paramount to extending the effectiveness of malaria vector control tools. Here, we demonstrate that a P450 haplotype spanning a Glu<sup>205</sup>→Asp (E205D) amino acid point mutation in the <i>CYP6P3</i> gene drives pyrethroid insecticide resistance in the mosquito malaria vector <i>Anopheles gambiae</i>. Pooled whole-genome DNA sequencing data from <i>A. gambiae</i> mosquitoes detected a major P450-linked locus (CYP6 haplotype) on chromosome 2R adjacent to the locus encoding a sodium channel. In vitro metabolism assays with recombinantly expressed CYP6P3 protein revealed that the catalytic efficiency of the 205D variant for the pyrethroid insecticide permethrin was 3.7 times higher than that of the E205 variant. Similar findings were made for the related insecticide α-cypermethrin. Overexpression of the 205D variant in transgenic flies conferred higher resistance to pyrethroids compared with flies expressing the susceptible E205 variant. A DNA-based assay confirmed that the <i>CYP6P3</i>-E205D variant correlates with pyrethroid resistance in field mosquito populations [odds ratio (OR): 26.4; <i>P</i> < 0.0001] and reduces the efficacy of pyrethroid-only long-lasting insecticide bed nets. The homozygous resistance genotype of <i>A. gambiae</i> exhibited higher survival after exposure to the PermaNet 3.0 bed net compared with the susceptible SS genotype (OR: 6.1; <i>P</i> = 0.011). Furthermore, the <i>CYP6P3</i>-E205D variant together with the <i>kdr</i> target-site resistance mechanism exacerbated the loss of bed net efficacy. The 205D variant is predominant in West and Central Africa but less abundant or absent in East and South Africa, with signs of introgression with <i>Anopheles coluzzii</i> in Ghana.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111407","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}
Endothelial dysfunction plays a critical role in the initiation and progression of vascular remodeling and pulmonary arterial hypertension (PAH). Sine oculis homeobox 1 (SIX1) is a developmentally restricted transcription factor, and its expression ceases upon the completion of embryonic development. Deletion of Six1 impairs the differentiation of pulmonary vascular endothelial cells, resulting in pulmonary vascular defects and postnatal death. In this study, we found that SIX1 was increased in the endothelia of pulmonary arteries from patients with PAH and from patients with idiopathic pulmonary fibrosis–associated pulmonary hypertension (PH). Silencing SIX1 using siRNA inhibited hypoxia-induced endothelial dysfunction in vitro, including proliferation, endothelial-to-mesenchymal transition, and endothelin-1 release. Endothelial-specific Six1 knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)–induced PH mice. Moreover, endothelial-specific Six1 overexpression mediated by adeno-associated virus induced a spontaneous PH in wild-type C57BL/6 mice. Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity. Zafirlukast suppressed hypoxia-induced endothelial dysfunction in vitro and reversed SuHx-induced PH in Sprague-Dawley rats. Mechanistically, multiomics profiling of hypoxia-induced endothelial dysfunction in vitro revealed that microtubule-associated serine/threonine kinase family member 4 (MAST4) was a target of SIX1. MAST4 phosphorylated the Thr185/202 sites of mitogen-activated protein kinases 1 and 3 (MAPK1/3), resulting in endothelial dysfunction. Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating MAST4 transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development.
{"title":"Sine oculis homeobox 1 drives endothelial dysfunction in preclinical pulmonary arterial hypertension","authors":"Ting Liu, Wei Zhou, Cheng Fang, Yao Liang, Zhenyu Zhao, Anqi Cai, Xueying Peng, Xiaoli Ye, Mengru Bai, Xiaoping Hu, Nengming Lin, Xiaozhou Zou, Ping Huang","doi":"10.1126/scitranslmed.adu6425","DOIUrl":"10.1126/scitranslmed.adu6425","url":null,"abstract":"<div >Endothelial dysfunction plays a critical role in the initiation and progression of vascular remodeling and pulmonary arterial hypertension (PAH). Sine oculis homeobox 1 (<i>SIX1</i>) is a developmentally restricted transcription factor, and its expression ceases upon the completion of embryonic development. Deletion of <i>Six1</i> impairs the differentiation of pulmonary vascular endothelial cells, resulting in pulmonary vascular defects and postnatal death. In this study, we found that SIX1 was increased in the endothelia of pulmonary arteries from patients with PAH and from patients with idiopathic pulmonary fibrosis–associated pulmonary hypertension (PH). Silencing <i>SIX1</i> using siRNA inhibited hypoxia-induced endothelial dysfunction in vitro, including proliferation, endothelial-to-mesenchymal transition, and endothelin-1 release. Endothelial-specific <i>Six1</i> knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)–induced PH mice. Moreover, endothelial-specific <i>Six1</i> overexpression mediated by adeno-associated virus induced a spontaneous PH in wild-type C57BL/6 mice. Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity. Zafirlukast suppressed hypoxia-induced endothelial dysfunction in vitro and reversed SuHx-induced PH in Sprague-Dawley rats. Mechanistically, multiomics profiling of hypoxia-induced endothelial dysfunction in vitro revealed that microtubule-associated serine/threonine kinase family member 4 (<i>MAST4</i>) was a target of SIX1. MAST4 phosphorylated the Thr<sup>185/202</sup> sites of mitogen-activated protein kinases 1 and 3 (MAPK1/3), resulting in endothelial dysfunction. Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating <i>MAST4</i> transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111404","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 : 2026-02-04DOI: 10.1126/scitranslmed.adr9382
Ivan J. Cohen, Audrey C. Bochi-Layec, Jean Lemoine, Scott Jenks, Pedram Bayat, Ki Hyun Kim, Huiwu Zhao, Ositadimma Ugwuanyi, Federico Stella, Guido Ghilardi, Giulia Gabrielli, Sarah McCuaig, Anastasia Iatrou, Elisavet Vlachonikola, Maria Karipidou, Eleni Bouziani, David Espie, Ranjani Ramasubramanian, Andreas Agathangelidis, Aditya Bhosale, Luca Paruzzo, Giovanni Medico, Bronte Kolar, Regina Bugrovsky, Puneeth Guruprasad, Li-Ping Wang, Jaryse Harris, Evgeny Arons, Yunlin Zhang, Raymone Pajarillo, Portia A. Kreiger, Chi-Ping Day, S. Cenk Sahinalp, Chih Hao Wu, Alessia Santi, Bria Fulmer, Marcos Cases, Matthew B. Palmer, Patrizia Porazzi, E. John Wherry, Robert J. Kreitman, Enrico Tiacci, Sokratis A. Apostolidis, Edward M. Behrens, Vijay Bhoj, Ignacio Sanz, Giorgio Inghirami, Stephen J. Schuster, Paolo Ghia, Kostas Stamatopoulos, Marco Ruella
Current US Food and Drug Administration–approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene IGHV4-34 are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34+ serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34+ malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34+ BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34+ HBL1 cell line–derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34+ SLE B cells and deplete IGHV4-34+ autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.
{"title":"Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells","authors":"Ivan J. Cohen, Audrey C. Bochi-Layec, Jean Lemoine, Scott Jenks, Pedram Bayat, Ki Hyun Kim, Huiwu Zhao, Ositadimma Ugwuanyi, Federico Stella, Guido Ghilardi, Giulia Gabrielli, Sarah McCuaig, Anastasia Iatrou, Elisavet Vlachonikola, Maria Karipidou, Eleni Bouziani, David Espie, Ranjani Ramasubramanian, Andreas Agathangelidis, Aditya Bhosale, Luca Paruzzo, Giovanni Medico, Bronte Kolar, Regina Bugrovsky, Puneeth Guruprasad, Li-Ping Wang, Jaryse Harris, Evgeny Arons, Yunlin Zhang, Raymone Pajarillo, Portia A. Kreiger, Chi-Ping Day, S. Cenk Sahinalp, Chih Hao Wu, Alessia Santi, Bria Fulmer, Marcos Cases, Matthew B. Palmer, Patrizia Porazzi, E. John Wherry, Robert J. Kreitman, Enrico Tiacci, Sokratis A. Apostolidis, Edward M. Behrens, Vijay Bhoj, Ignacio Sanz, Giorgio Inghirami, Stephen J. Schuster, Paolo Ghia, Kostas Stamatopoulos, Marco Ruella","doi":"10.1126/scitranslmed.adr9382","DOIUrl":"10.1126/scitranslmed.adr9382","url":null,"abstract":"<div >Current US Food and Drug Administration–approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene <i>IGHV4-34</i> are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34<sup>+</sup> serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34<sup>+</sup> malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34<sup>+</sup> BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34<sup>+</sup> HBL1 cell line–derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34<sup>+</sup> SLE B cells and deplete IGHV4-34<sup>+</sup> autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111406","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}
Dysregulation of RNA N6-methyladenosine (m6A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m6A reader. We provided a high-resolution cocrystal structure of the YTHDC1–YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m6A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m6A readers is a potential strategy in the treatment of hematologic cancers.
{"title":"Small-molecule inhibition of YTHDC1 as a strategy against acute myeloid leukemia in mouse models","authors":"Hailin Zhang, Yueshan Li, Yin Zhao, Falu Wang, Guifeng Lin, Ting Niu, He Li, Yueyue Li, Lina Liu, Yue Liang, Yu Shen, Yuyao Yi, Hui Zhou, Shang Lou, Yishan Ye, Yanmin He, Ruicheng Yang, Rui Yao, Chenyu Tian, Pei Zhou, Mengdan Wu, Mingxin Chen, Haixing Xu, Jing You, Yi Liao, Chenlu Yang, Ailin Zhao, Chong Chen, Linli Li, Shanshan Pei, Shengyong Yang","doi":"10.1126/scitranslmed.adu3137","DOIUrl":"10.1126/scitranslmed.adu3137","url":null,"abstract":"<div >Dysregulation of RNA N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m<sup>6</sup>A reader. We provided a high-resolution cocrystal structure of the YTHDC1–YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m<sup>6</sup>A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m<sup>6</sup>A readers is a potential strategy in the treatment of hematologic cancers.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 835","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111401","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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