The Journal of Clinical Investigation最新文献_第3页

Targeting the PRMT5-Nur77 methylation axis enhances endometrial decidualization capacity and female fertility in preclinical models. 在临床前模型中，靶向PRMT5-Nur77甲基化轴增强子宫内膜去个体化能力和女性生育能力。

The Journal of Clinical Investigation Pub Date : 2026-07-16 DOI: 10.1172/jci178862

Zhiwen Cao,Xinyu Cai,Jie Mei,Na Kong,Yang Liu,Xiaoyue Shen,Min Wu,Xin Zhen,Jianxin Sun,Rong Li,Ruiwei Jiang,Haixiang Sun,Guijun Yan

{"title":"Targeting the PRMT5-Nur77 methylation axis enhances endometrial decidualization capacity and female fertility in preclinical models.","authors":"Zhiwen Cao,Xinyu Cai,Jie Mei,Na Kong,Yang Liu,Xiaoyue Shen,Min Wu,Xin Zhen,Jianxin Sun,Rong Li,Ruiwei Jiang,Haixiang Sun,Guijun Yan","doi":"10.1172/jci178862","DOIUrl":"https://doi.org/10.1172/jci178862","url":null,"abstract":"Defective endometrial decidualization is one major cause of female infertility, yet the underlying mechanisms remain elusive. Here, we identified that protein arginine methyltransferase 5 (PRMT5) which was upregulated during decidualization and by progesterone stimulation, is markedly down-regulated in the endometria of patients with recurrent implantation failure (RIF), along with a global reduction of symmetric dimethylarginine (sDMA). Uterine stromal-specific ablation of Prmt5 in mouse severely impaired decidualization leading to infertility. A multi‑omics analysis in human endometrial stromal cells (EnSCs) revealed that PRMT5 promoted decidualization primarily by catalyzing sDMA at arginine 346 (R346) of the orphan nuclear receptor Nur77, which directs its proper chromatin occupancy. Targeting the PRMT5-Nur77 methylation axis, we designed a peptide, Pep‑Nur77-R346K, which rescued the decidualization of multiple preclinical models: PRMT5 deficient human EnSCs, both genetic knockout (Prmt5d/d) and pharmacologically inhibited mouse models, an estrogen deficient mouse model, and, more importantly, the primary RIF EnSCs. In a retrospective cohort of 114 participants, the correlated reductions of endometrial PRMT5/Nur77-R346me2s was confirmed, which demonstrated robust predictive value for pregnancy outcome. Our work establishes the PRMT5‑Nur77 methylation axis as a key regulator of endometrial receptivity, and highlights both a novel diagnostic biomarker and a peptide‑based therapeutic potential for fertility.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapy-resistant lymphomas may want nucleotides, but they just need to grow. 治疗抵抗性淋巴瘤可能需要核苷酸，但它们只需要生长。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci208384

Carlos Carmona-Fontaine

引用次数: 0

The bone-cerebrovascular axis: effects of bone aging on neurovascular dysfunction and neurodegeneration. 骨-脑血管轴：骨老化对神经血管功能障碍和神经变性的影响。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci207273

Jiekang Wang,Xu Cao,Mei Wan

{"title":"The bone-cerebrovascular axis: effects of bone aging on neurovascular dysfunction and neurodegeneration.","authors":"Jiekang Wang,Xu Cao,Mei Wan","doi":"10.1172/jci207273","DOIUrl":"https://doi.org/10.1172/jci207273","url":null,"abstract":"Beyond serving as a structural organ, the skeleton undergoes continuous remodeling and functions as an endocrine organ by secreting bioactive factors that regulate the physiology of distant tissues. Indeed, the concept of a \"bone-vascular axis\" has long been recognized, supported by epidemiological evidence linking osteoporosis and low bone mass to increased cardiovascular morbidity and mortality. Emerging findings now extend this paradigm to the brain, suggesting that bone- and bone marrow-derived signals influence cerebrovascular structure, function, and aging. Given that cerebrovascular dysfunction is a central driver of age-related cognitive decline, dementia, and neurodegenerative diseases, understanding this \"bone-cerebrovascular axis\" may offer novel opportunities for prevention and intervention. Here, we outline the cellular and molecular mechanisms underlying age-associated neurovascular impairment and summarize the biology of major bone and bone marrow cell populations, with emphasis on age-related alterations in their secretome. A central focus of this Review is the emerging evidence that age-related skeletal alterations exert systemic effects on the cerebrovasculature, highlighting how bone- and bone marrow-derived factors shape neurovascular health and pathology, which may subsequently contribute to CNS aging and neurodegeneration. A deeper understanding of these systemic interactions reframes brain aging within a whole-body context and may uncover innovative biomarkers and therapeutic strategies to mitigate neurodegeneration and other age-associated disorders.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cholesterol-responsive NFE2L1-INSIG1 interaction controls VLDL secretion and metabolic dysfunction-associated steatohepatitis pathogenesis in mice. 胆固醇反应性NFE2L1-INSIG1相互作用控制小鼠VLDL分泌和代谢功能障碍相关的脂肪性肝炎发病机制。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci197094

Shijun Deng,Jessica E Freed,Grace Y Lee,Gizel Askin,Zhe Cao,Özgür Cakici,Bo Yuan,Sheng Tony Hui,Karen E Inouye,Isabel Graupera,Gökhan S Hotamışlıgil

{"title":"Cholesterol-responsive NFE2L1-INSIG1 interaction controls VLDL secretion and metabolic dysfunction-associated steatohepatitis pathogenesis in mice.","authors":"Shijun Deng,Jessica E Freed,Grace Y Lee,Gizel Askin,Zhe Cao,Özgür Cakici,Bo Yuan,Sheng Tony Hui,Karen E Inouye,Isabel Graupera,Gökhan S Hotamışlıgil","doi":"10.1172/jci197094","DOIUrl":"https://doi.org/10.1172/jci197094","url":null,"abstract":"Cholesterol overload contributes to metabolic dysfunction-associated steatohepatitis (MASH) progression. One major pathway that limits hepatic cholesterol accumulation is export via VLDL secretion. While sterol regulatory element-binding protein (SREBP) activity is suppressed by insulin-induced gene 1 (INSIG1) under high sterol conditions, VLDL secretion nonetheless persists to prevent lipotoxicity and liver injury, presenting an unresolved paradox in cholesterol sensing and lipoprotein export. Here, we identified a cholesterol-responsive interaction between nuclear factor erythroid 2 related factor-1 (NFE2L1) and INSIG1 that preserved cholesterol homeostasis by sustaining VLDL secretion. Liver-specific NFE2L1 deletion elevated INSIG1 abundance, suppressed SREBP1 activation, and impaired VLDL secretion, leading to hepatic cholesterol accumulation and liver injury. Mechanistically, NFE2L1 bound to INSIG1 via its N-terminal homology box 2 (NHB2) domain; free cholesterol strengthened this interaction to promote INSIG1 degradation, thereby enabling SREBP1 activation and VLDL export. In NFE2L1-deficient mice, WT NFE2L1, but not a mutant NFE2L1 form unable to interact with INSIG1 (NHB2-deleted mutant, ΔNHB2), restored SREBP1 activity and VLDL secretion. Lipidomics analysis revealed that NFE2L1 deficiency reduced serum triglyceride composition, which was restored exclusively by WT NFE2L1. In a murine MASH model, NFE2L1 overexpression activated SREBP1/2, lowered hepatic cholesterol, and attenuated liver injury, inflammation, and fibrosis, without elevating atherogenic lipoproteins owing to compensatory LDL receptor upregulation. Together, these findings explain how VLDL secretion capacity was maintained under cholesterol excess and identify the NFE2L1/INSIG1 axis as a sterol-responsive safeguard for hepatic lipid homeostasis and a potential therapeutic target for MASH.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Kevin N. Sheth, MD, receives the 2026 Bruce F. Scharschmidt and Peggy S. Crawford Translational Medicine Award. 医学博士Kevin N. Sheth获得2026 Bruce F. Scharschmidt和Peggy S. Crawford转化医学奖。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci209633

引用次数: 0

The splice of life: an isoform-centric view of disease, technology, and therapeutics. 生命的拼接：疾病、技术和治疗的异构体中心观。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci207476

Timothy Pan,Lina Lu,Ruli Gao

{"title":"The splice of life: an isoform-centric view of disease, technology, and therapeutics.","authors":"Timothy Pan,Lina Lu,Ruli Gao","doi":"10.1172/jci207476","DOIUrl":"https://doi.org/10.1172/jci207476","url":null,"abstract":"Alternative splicing is a pervasive mechanism that expands the coding potential and functional complexity of the human genome. Dysregulated isoform usage alters gene functions and contributes broadly to human disease across developmental, neurodegenerative, and cancer settings. Technologies for characterizing splicing and isoforms have advanced rapidly, evolving from Sanger sequencing of individual cDNA clones to high-throughput next-generation sequencing of splice junctions, and more recently to long-read sequencing that resolves full-length transcripts at bulk, single-cell, and spatial resolutions. With the growing recognition of their critical roles in human disease, multiple therapeutic modalities have been developed to precisely target splicing and isoform regulation at the DNA, RNA, and protein levels. Clinical-grade small molecules and antisense oligonucleotides that modulate aberrant RNA splicing and isoform switching have become available, offering new hope for previously incurable diseases. Here, we review this crucial yet underexplored layer of transcriptomic regulation in human disease, encompassing regulatory mechanisms, technological advances, therapeutic strategies, and future directions.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"250 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Winners of Lasker Foundation Video Contest announced. 拉斯克基金会视频比赛获奖名单揭晓。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci210286

Mitch Leslie

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SEC16B identified as a regulator of VLDL secretion and lipid accumulation in the liver. SEC16B被认为是肝脏中VLDL分泌和脂质积累的调节因子。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci208521

Hossein Ardehali

引用次数: 0

Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti-PD-L1 refractoriness in breast cancer models. 在乳腺癌模型中，骨桥蛋白介导对缺氧诱导的抗血管生成的获得性抵抗并促进抗pd - l1的难治性。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci174092

Jose Luis Ruiz-Sepulveda,Maria J Bueno,Silvana Mouron,Veronica Jimenez-Renard,Manuel Muñoz,Manuel Moradiellos,Leonardo D Garma,Luis García-Jimeno,Adam W Watson,Ghassan Mouneimne,Solip Park,Rebeca Jimeno,Miguel Quintela-Fandino

{"title":"Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti-PD-L1 refractoriness in breast cancer models.","authors":"Jose Luis Ruiz-Sepulveda,Maria J Bueno,Silvana Mouron,Veronica Jimenez-Renard,Manuel Muñoz,Manuel Moradiellos,Leonardo D Garma,Luis García-Jimeno,Adam W Watson,Ghassan Mouneimne,Solip Park,Rebeca Jimeno,Miguel Quintela-Fandino","doi":"10.1172/jci174092","DOIUrl":"https://doi.org/10.1172/jci174092","url":null,"abstract":"Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we showed that hypoxia-inducing anti-VEGF therapy upregulated programmed cell death ligand 1 (PD-L1), yet failed to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggered epithelial osteopontin (SPP1) production, which recruited monocytes and skewed macrophages toward M2 states, suppressing T cell cytotoxicity. Pharmacological SPP1 depletion impeded the development of hypoxia, reduced M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenics and anti-PD-L1. Genetic dissection - tumor-epithelial Spp1-KO grafts and bone marrow chimeras generated by lethal irradiation and reconstitution with Spp1-/- or WT hematopoietic donors - showed that myeloid SPP1 contributed only marginally compared with epithelial SPP1. These findings identified SPP1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contributed to a comprehensive model of antiangiogenic resistance, and supported SPP1-targeted strategies to personalize immunotherapy and antiangiogenic therapy according to tumor hypoxia.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation. slc15a3介导的二肽代谢通过mTORC1激活赋予淋巴瘤抗代谢物抗性。

The Journal of Clinical Investigation Pub Date : 2026-07-15 DOI: 10.1172/jci199709

Haojun Yang,Vincenzo Andrea Zingaro,Kevin Boardman,Ashish Noronha,Ekin Guney,Lingru Xue,Saishma Hoigebazar,Isabelle Liu,Sohit Miglani,Siyu Chen,Hieu Vu,Kwun Wah Wen,Hao G Nguyen,Hani Goodarzi,Ralph J DeBerardinis,Davide Ruggero

{"title":"SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.","authors":"Haojun Yang,Vincenzo Andrea Zingaro,Kevin Boardman,Ashish Noronha,Ekin Guney,Lingru Xue,Saishma Hoigebazar,Isabelle Liu,Sohit Miglani,Siyu Chen,Hieu Vu,Kwun Wah Wen,Hao G Nguyen,Hani Goodarzi,Ralph J DeBerardinis,Davide Ruggero","doi":"10.1172/jci199709","DOIUrl":"https://doi.org/10.1172/jci199709","url":null,"abstract":"Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. A similar mechanism occurred after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrated that dipeptides containing essential amino acids activated the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored resistant lymphoma sensitivity to 6MP. Strikingly, resistant lymphomas, but not primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, in culture and in vivo. We extended these findings in human lymphoma biopsies, which revealed increased SLC15A3 expression following antimetabolite therapy. Together, our study uncovered a metabolic adaptation that fuels cancer resistance to nucleotide deficiency and positions the mTORC1 inhibitor, rapamycin, as a potential therapeutic strategy for transforming the management of chemotherapy-resistant lymphomas.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"447 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148441167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0