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Commentary

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A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer
Samyuktha Suresh, James M. Ford
Samyuktha Suresh, James M. Ford
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e193171. https://doi.org/10.1172/JCI193171.
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A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer

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Abstract

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, presents a clinical challenge in developing effective treatment options. In this issue of the JCI, Zeng et al. demonstrate a provocative and promising therapeutic strategy for TNBC by leveraging the metabolic vulnerabilities presented by methylthioadenosine phosphorylase (MTAP) deletion to genotoxic stress inducers, such as poly (ADP-ribose) polymerase inhibitors (PARPi). They found that combining MTAP deletion or inhibition with PARPi was highly effective in brain metastatic TNBC where the methionine-limited environment further enhanced this combination. This approach underscores the importance of targeting metabolic vulnerabilities in the development of personalized cancer therapies.

Authors

Samyuktha Suresh, James M. Ford

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Thwarting amyloidosis: IL-17 as a disease modifier along the gut/brain axis
Wade K. Self, David M. Holtzman
Wade K. Self, David M. Holtzman
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e194443. https://doi.org/10.1172/JCI194443.
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Thwarting amyloidosis: IL-17 as a disease modifier along the gut/brain axis

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Abstract

Recent studies have highlighted a possible role for gut microbiota in modulating Alzheimer’s disease pathology, particularly through the actions of gut-derived metabolites and their influence on the immune system. In this issue of the JCI, Chandra et al. reveal that circulating levels of the gut microbiota–derived metabolite propionate affected amyloid burden and glial activation in a mouse model of Aβ amyloidosis. The study also identifies a mechanism for the therapeutic benefit of propionate supplementation, showing that propionate lowered peripheral IL-17 and suppressed Th17 cell activity. These results support the idea of therapeutic targeting of the gut/brain/immune axis, particularly via modulation of Th17 responses, and suggest translational strategies involving microbiome-based or immunological interventions for dementia prevention and treatment.

Authors

Wade K. Self, David M. Holtzman

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Should GLP-1 receptor agonist therapy be used to treat obesity in Bardet-Biedl syndrome?
Jeremy W. Tomlinson
Jeremy W. Tomlinson
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e191822. https://doi.org/10.1172/JCI191822.
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Should GLP-1 receptor agonist therapy be used to treat obesity in Bardet-Biedl syndrome?

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Abstract

Bardet-Biedl syndrome (BBS) is a complex genetic condition that can affect multiple organ systems, frequently causing pigmentary retinopathy, renal abnormalities, polydactyly, and obesity. Metabolic disturbances including obesity, unsuppressed appetite, and an increased risk of type 2 diabetes (T2D) present clinical management challenges. In this issue of the JCI, Singh et al. present a mouse model of a specific BBS subtype with genetic deletion of the Bbs5 gene. The model recapitulates many of the clinical features observed in patients living with BBS5 and sheds light on adipocyte biology, as well as the hypothalamic mechanisms driving hunger- and food-seeking behaviors that fuel the adverse metabolic phenotype. Importantly, exogenous GLP-1 receptor agonist treatment suppressed both appetite and weight, opening opportunities for direct translation into the clinical setting.

Authors

Jeremy W. Tomlinson

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Uromodulin modulates mitochondria and kidney tubule resilience
Ronak Lakhia, … , Chunzi Song, Vishal Patel
Ronak Lakhia, … , Chunzi Song, Vishal Patel
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e193829. https://doi.org/10.1172/JCI193829.
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Uromodulin modulates mitochondria and kidney tubule resilience

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Abstract

Uromodulin is the most abundant protein in human urine, playing diverse roles, from providing frontline defense against uropathogens to regulating electrolyte balance via modulation of ion channels and cotransporters. In this issue of the JCI, Nanamatsu et al. unveil an alternatively spliced isoform of uromodulin that was dynamically induced in response to oxidative stress and tubular injury. Unlike the canonical secreted form, this isoform was retained in the cell, where it interacted with solute carrier proteins primarily localized to the mitochondrial membrane. Through these interactions, it modulated mitochondrial energetics and enhanced tubular cell resilience to injury. These findings broaden our understanding of uromodulin’s multifaceted functions, uncover an adaptive mechanism by which the kidney responds to cellular stress, and open avenues for therapeutic strategies targeting kidney injury and repair.

Authors

Ronak Lakhia, Chunzi Song, Vishal Patel

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Microglia matters: visualizing the immune battle in Parkinson’s disease
So Jeong Lee, … , Changning Wang, Jacob Hooker
So Jeong Lee, … , Changning Wang, Jacob Hooker
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e192919. https://doi.org/10.1172/JCI192919.
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Microglia matters: visualizing the immune battle in Parkinson’s disease

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Abstract

Microglia play critical roles in immune defense within the central nervous system (CNS), and microglia-mediated immune changes in the brain are observed in various neurodegenerative diseases, including Parkinson’s disease (PD). While PET imaging with a range of radiolabeled ligands has been invaluable for visualizing and quantifying neuroimmune changes in the brains of patients with PD, no PET ligands currently exist that are specific to microglia. In this issue of the JCI, Mills et al. used the PET radioligand [¹¹C]CPPC to image colony stimulating factor 1 receptor (CSF1R), revealing a connection between increased CSF1R expression and microglia-mediated brain immune changes in patients with PD. The study demonstrated that elevated CSF1R expression colocalized with a microglial-specific marker in brain regions vulnerable to PD. Moreover, quantifying CSF1R density with [¹¹C]CPPC-PET imaging in living brains may provide an indicator of motor and cognitive impairments in the early stages of PD. These findings underscore the potential of CSF1R-PET imaging as a microglial-sensitive biomarker of brain immune function in PD.

Authors

So Jeong Lee, Changning Wang, Jacob Hooker

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Regular meals matter: bone growth and beyond
Rhonda D. Kineman, Shoshana Yakar
Rhonda D. Kineman, Shoshana Yakar
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e194079. https://doi.org/10.1172/JCI194079.
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Regular meals matter: bone growth and beyond

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Abstract

The effect of food intake patterns on growth remain largely unknown. In this issue of the JCI, Hornsby et al. provide compelling evidence that, in young males, confining food intake to three meals a day entrains preprandial ghrelin release, leading to postprandial growth hormone pulse release that is associated with an increase in epiphysial plate expansion — a measure indicative of increased bone growth. The positive effects of discrete meal intake, on bone, was dependent on an intact ghrelin signaling system. This Commentary posits that meal-entrained ghrelin release may enhance skeletal accrual, whether through direct action on bone cells, via stimulation of growth hormone secretion, or in concert with other nutrient-responsive hormones. Coordinating these hormonal cues with food intake could maximize bone acquisition and improve bone health throughout the lifespan.

Authors

Rhonda D. Kineman, Shoshana Yakar

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Therapeutic B cell depletion identifies immunoregulatory networks
Carolina M. Polonio, Francisco J. Quintana
Carolina M. Polonio, Francisco J. Quintana
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e189442. https://doi.org/10.1172/JCI189442.
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Therapeutic B cell depletion identifies immunoregulatory networks

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Abstract

B cell depletion is a highly effective therapy in multiple sclerosis (MS), reducing inflammation and restoring immune balance. In this issue of the JCI, Wei et al. used single-cell RNA-Seq and flow cytometry, identifying the comprehensive effects of B cell depletion on the immune response, including an increase in antiinflammatory cerebrospinal fluid macrophages and elevated TNF-α expression by peripheral CD16+ monocytes. The authors also detected shifts in T cell populations that resulted in reduced myelin-reactive CD4+ T cells and the expansion of TIGIT+ Tregs. The findings uncover immunoregulatory mechanisms and suggest therapeutic strategies for MS and other autoimmune disorders.

Authors

Carolina M. Polonio, Francisco J. Quintana

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The writing on the arterial wall: epigenetic control of blood pressure and vascular remodeling
Lloyd D. Harvey, Stephen Y. Chan
Lloyd D. Harvey, Stephen Y. Chan
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e194839. https://doi.org/10.1172/JCI194839.
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The writing on the arterial wall: epigenetic control of blood pressure and vascular remodeling

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Abstract

Hypertension is a leading cause of morbidity and mortality, with pathologic consequences on multiple end-organ systems. Smooth muscle plasticity and its epigenetic regulation promote disease pathogenesis, but the genetic levers that control such activity are incompletely defined. In this issue of the JCI, Mangum et al. utilized high-density genomic data to define the causal and pathogenic role of a variant at the JMJD3 locus — one that is associated with systolic blood pressure and governs an allele-specific molecular mechanism controlling smooth muscle behavior in hypertension. These findings have clinical implications relevant to patient risk stratification and personalized therapeutics.

Authors

Lloyd D. Harvey, Stephen Y. Chan

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Another Fanconi anemia gene joins the club
Claire C. Homan, … , Hamish S. Scott, Parvathy Venugopal
Claire C. Homan, … , Hamish S. Scott, Parvathy Venugopal
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e192382. https://doi.org/10.1172/JCI192382.
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Another Fanconi anemia gene joins the club

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Abstract

Fanconi anemia (FA) is the most common inherited bone marrow failure disorder, caused by pathogenic variants in genes involved in the FA DNA repair pathway. In this issue of the JCI, two studies report three germline homozygous loss-of-function variants in FAAP100, a key component of the FA core complex, identified in three unrelated families. These variants result in severe developmental phenotypes that are among the most extreme reported in FA to date. Harrison et al. described individuals from two families with recurrent pregnancy loss and neonatal death due to homozygous FAAP100 frameshift and truncating variants, respectively. Kuehl et al. identified a homozygous missense variant in a fetus with congenital malformations consistent with FA. Collectively, both studies provide robust functional evidence from ex vivo and in vitro assays with animal models supporting the pathogenicity of these variants and establish FAAP100 as a causative FA gene.

Authors

Claire C. Homan, Hamish S. Scott, Parvathy Venugopal

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Switching on the evolutionary potential of pancreatic cancer: the tumor suppressor functions of PBRM1
Luigi Perelli, Giannicola Genovese
Luigi Perelli, Giannicola Genovese
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e193205. https://doi.org/10.1172/JCI193205.
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Switching on the evolutionary potential of pancreatic cancer: the tumor suppressor functions of PBRM1

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Abstract

Cell plasticity is a hallmark of cancer, enabling tumor cells to acquire multiple phenotypes responsible for tumor progression, metastasis, and therapy resistance. In this issue of the JCI, Kawai and colleagues leveraged genetically engineered mouse models (GEMM) of pancreatic ductal adenocarcinoma (PDAC) to demonstrate that loss of Pbrm1, a member of the SWI/SNF complex, drives dedifferentiation and aggressive tumor features. Pbrm1 loss activated a program of epithelial-to-mesenchymal transition (EMT) and allowed the emergence of poorly differentiated histologies that are commonly associated with high recurrence rate and dismal prognosis. These findings reveal the role of the SWI/SNF complex during PDAC evolution in maintaining cell identity and restraining the progression of this lethal disease.

Authors

Luigi Perelli, Giannicola Genovese

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