Xu X, Zhou Y, Xu S
… +8 more, Zhou H, Lin X, Luo Y, Xu Y, Miao Z, Ge W, Yang H, Xu X
J Clin Invest
· 2026 May · PMID 42138082
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Skraban-Deardorff syndrome, a rare neurodevelopmental disorder caused by WD repeat domain 26 (WDR26) haploinsufficiency, is characterized by intellectual disability, seizures, autistic-like behaviors, and craniofacial an...Skraban-Deardorff syndrome, a rare neurodevelopmental disorder caused by WD repeat domain 26 (WDR26) haploinsufficiency, is characterized by intellectual disability, seizures, autistic-like behaviors, and craniofacial anomalies. Despite its genetic association with variants disrupting the C-terminal to LisH (CTLH) E3 ubiquitin ligase complex, the molecular mechanisms linking WDR26 dysfunction to neurodevelopmental deficits remain unclear. Here, we demonstrate that Wdr26 heterozygous-KO mice (Wdr26+/-) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities. Mechanistically, Wdr26 haploinsufficiency stabilized RUNX1 translocation partner 1 (RUNX1T1), a transcriptional coactivator critical for neuronal differentiation, by impairing its ubiquitination and proteasomal degradation, consequently disrupting the level of microtubule-associated protein 2 (MAP2), a key regulator of dendritic architecture and synaptic plasticity. Early intervention in neonatal Wdr26+/- mice (P0.5) using AAV-shRNA-mediated Runx1t1 knockdown reversed MAP2 overexpression and behavioral deficits. Notably, the antipsychotic risperidone ameliorated cognitive and social impairments in Wdr26+/- mice by upregulating WDR26 levels, suggesting a potential therapeutic avenue. Our findings not only establish the animal model as a robust preclinical tool but also define the WDR26/RUNX1T1/MAP2 regulatory axis as pivotal to the syndrome's pathogenesis, while identifying actionable therapeutic targets.
J Clin Invest
· 2026 May · PMID 42138081
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Clinical management of pancreatic cancer (PC) remains severely limited, primarily due to the complex tumor microenvironment. Emerging DNA damage-targeted strategies have demonstrated considerable therapeutic potential in...Clinical management of pancreatic cancer (PC) remains severely limited, primarily due to the complex tumor microenvironment. Emerging DNA damage-targeted strategies have demonstrated considerable therapeutic potential in PC. In this issue of the JCI, Teh et al. employed cancer-specific multitarget sgRNAs to induce DNA double-strand breaks (DSBs), resulting in lethal effects in PC cells. Integrative bioinformatic and cytogenetic analyses revealed that CRISPR/Cas9-mediated DSBs provoked persistent chromosomal instability, ultimately leading to chromosome catastrophe and cell death. Compared with equivalent radiation-induced DSBs, these sgRNAs exhibited superior cytotoxicity and were able to eliminate cells resistant to a specific sgRNA via subsequent targeting at distinct genomic sites, highlighting a promising and innovative precision therapeutic approach for clinical treatment of PC.
J Clin Invest
· 2026 May · PMID 42138080
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Type 1 diabetes mellitus (T1D) has been recognized as a chronic autoimmune disease for five decades, but therapy has relied on the exogenous replacement of insulin, which is an imperfect substitute for normal β cell func...Type 1 diabetes mellitus (T1D) has been recognized as a chronic autoimmune disease for five decades, but therapy has relied on the exogenous replacement of insulin, which is an imperfect substitute for normal β cell function. In recent years, there has been progress in the development of new therapeutics that target the primary causes of the disease: failed immunologic tolerance and β cell killing. One agent, teplizumab, was shown to attenuate loss of β cell function that occurs over time and delay progression to clinical disease in individuals at risk, leading to its regulatory approval in 2022. Other immunologic agents show promise in modulating the immunologic imbalance. Moreover, a role for β cells in T1D pathogenesis has been identified and may be targeted. Now that the first disease-modifying therapeutic agent is available, future studies may involve combinations of agents to extend immunologic tolerance and protect and restore β cells so that lasting metabolic remission can be achieved.
Urano F, Marshall BA, Hurst S
… +10 more, Robichaux-Viehoever A, Ahmadi S, Hershey T, Van Stavern G, Cruz Bravo P, Powers Carson J, Pesko J, Fox K, Erpelding N, Bedrosian CL
J Clin Invest
· 2026 May · PMID 42138079
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PB&TURSO was associated with improved or stabilized pancreatic function, vision, and overall symptom burden in individuals with Wolfram syndrome, a rare and progressive degenerative disease.PB&TURSO was associated with improved or stabilized pancreatic function, vision, and overall symptom burden in individuals with Wolfram syndrome, a rare and progressive degenerative disease.
Kim TW, Piao J, Bocchi VD
… +19 more, Koo SY, Choi SJ, Chaudhry F, Yang D, Cho HS, Hergenreder E, Ruiz Perera L, Joshi S, Abou Mrad Z, Claros N, Donohue SA, Eun Im Y, Jeong HJ, Frank AK, Walsh RM, Mosharov EV, Betel D, Tabar V, Studer L
J Clin Invest
· 2026 May · PMID 42138078
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While clinical trials of human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts for Parkinson's disease (PD) are ongoing, current protocols remain suboptimal. In particular, the yield of TH+...While clinical trials of human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts for Parkinson's disease (PD) are ongoing, current protocols remain suboptimal. In particular, the yield of TH+ mDA neurons after in vivo grafting and the expression of certain mDA neuron and subtype-specific markers require improvement. Single-cell transcriptomic analyses of grafts have revealed low proportions of mDA neurons and substantial off-target contamination. Here, we present an optimized mDA neuron differentiation strategy that builds on our clinical-grade ("Boost") protocol by adding FGF18 and IWP2 treatment ("Boost+") at the neurogenesis stage. Boost+ mDA neurons show higher expression of EN1, PITX3, and ALDH1A1. Improvements in mDA neuron yield and transcriptional similarity to primary mDA neurons are observed in vitro and following transplantation. Single-nucleus RNA sequencing demonstrates enrichment of A9 mDA neurons within Boost+ grafts. Functional studies in vitro demonstrate increased dopamine production and release and improved electrophysiological properties. In vivo analyses show higher percentages of TH+ mDA neurons, resulting in efficient rescue of amphetamine-induced rotation behavior in the 6-OHDA rat model and rescue of deficits in some nondrug-induced assays, including the ladder rung assay, which are not improved by Boost mDA neurons. The Boost+ conditions present an optimized differentiation protocol with advantages for disease modeling and mDA neuron grafting paradigms.
Haddad G, Guo J, Xi Y
… +10 more, Albayrak E, Huseni M, Hamidi H, Banchereau R, Kadel E, Dubey S, Carter C, Kapur P, Brugarolas J, Pedrosa I
J Clin Invest
· 2026 May · PMID 42138077
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BACKGROUNDThe relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood.METHODSWe analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC...BACKGROUNDThe relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood.METHODSWe analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC patients in the IMmotion150 phase II clinical trial, where patients were randomized to atezolizumab, atezolizumab/bevacizumab, or sunitinib.RESULTSAngiogenic tumors (clusters 1 and 2) had a higher rate of pancreatic (21% vs. 6.9%; P = 0.002) and lower absolute number of lymph node (2.5 vs. 4.2; P = 0.006) metastases. In contrast, proliferative tumors (clusters 4 and 5) exhibited a higher absolute number of lymph node metastases (5.5 vs. 3.5; P = 0.019). Patients with pancreatic metastases receiving sunitinib had higher odds of overall response (OR, 7.13; 95% CI, 1.81-28.07; P = 0.0049) and longer progression-free survival than those without pancreatic metastases (P = 0.02).CONCLUSIONccRCC metastatic tropism relates to molecular clusters that predict response to therapy for tumors that metastasize to the pancreas.TRIAL REGISTRATIONClinicalTrials.gov NCT01984242FUNDINGNIH grants R01CA154475 and P50CA196516.
Hale AT, Kundishora AJ, Kalailingam P
… +11 more, Barak T, Duy PQ, Ramundo CM, Fan B, Li Q, Brastianos PK, Shankar GM, Alper SL, Kleinstiver BP, Musolino PL, Kahle KT
J Clin Invest
· 2026 May · PMID 42138076
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Recent advances in cerebrovascular genomics, single-cell biology, pharmacology, and gene editing technology are transforming our understanding of brain arteriovenous malformations (bAVMs) - a leading cause of pediatric h...Recent advances in cerebrovascular genomics, single-cell biology, pharmacology, and gene editing technology are transforming our understanding of brain arteriovenous malformations (bAVMs) - a leading cause of pediatric hemorrhagic stroke. Once considered static anatomical defects, bAVMs are now recognized as dynamic, genetically driven lesions resulting from somatic mutations in KRAS, BRAF, and pathways involved in arteriovenous specification, angiogenesis, and vascular remodeling. By integrating human genetics, animal models, and endovascular innovations, researchers have uncovered convergent mechanisms that link endothelial Ras/MAPK hyperactivation to abnormal vessel growth and higher rupture risk. These insights provide a foundation for precision medicine approaches that combine molecular diagnostics - such as liquid or endoluminal biopsies - with mutation-specific pharmacotherapies and emerging CRISPR-based gene editing strategies. We suggest that genotype-guided interventions, tailored by spatial and developmental cerebrovascular context, could ultimately reclassify bAVMs from surgically incurable malformations to treatable molecular conditions.
J Clin Invest
· 2026 May · PMID 42138075
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Glioma stem cells (GSCs) are a small subset of self-renewing, plastic, and multipotent neoplastic cells in glioblastoma (GBM) that sit at the apex of a cellular differentiation hierarchy. Elucidating pathways that enhanc...Glioma stem cells (GSCs) are a small subset of self-renewing, plastic, and multipotent neoplastic cells in glioblastoma (GBM) that sit at the apex of a cellular differentiation hierarchy. Elucidating pathways that enhance GSC properties and determine their cell-specific interactions within the immunosuppressive GBM microenvironment are critical for developing effective therapeutic approaches. The CLOCK-BMAL1 complex, which is well known for its activity as a circadian rhythm-regulating transcription factor, plays a critical role in maintaining GSC stemness, and the gene encoding CLOCK was found to be amplified in about 5% of GBM cases. Here, Zhou et al. have uncovered a "symbiotic exclusivity" relationship between CLOCK-BMAL1 and TFPI2, which is also amplified in a small proportion of GBM cases. This relationship forms a HIF-1α/NF-κB P65-mediated positive feedback loop that boosts the proliferative and tumor-enhancing capacities of GSC and immunosuppressive microglia. This self-amplifying regulatory circuit represents an opportunity for intervention to inhibit GBM growth.
J Clin Invest
· 2026 May · PMID 42138074
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Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects...Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects of cachexia. The search for circulating mediators of cancer cachexia has focused largely on secreted proteins, but metabolites may also drive systemic wasting. In this issue, Morigny, Rohm, and colleagues identified the liver as a major source of circulating ceramides in cachectic mice and patients with cancer and demonstrated that inhibiting ceramide synthesis attenuated muscle wasting and preserved function in cachectic mice. These findings position the liver as an endocrine organ in cachexia and introduce a druggable metabolic pathway with translational potential.
Morigny P, Ji H, Cussonneau L
… +32 more, Zorzato S, Kwon Y, Riols F, Kaltenecker D, Maier A, Karthikaisamy V, Corrà S, Krauss T, Seeliger C, Gillani SQ, Tissink JJ, Lacas-Gervais S, Samanci TF, Maida A, Terron-Exposito R, Trinca A, von Toerne C, Nogara L, Claussnitzer M, Prokopchuk O, Bachmann J, Berriel Diaz M, Bindels LB, Kuda O, Hauner H, Haid M, Herzig S, Viscomi CF, Gilleron J, Zeigerer A, Blaauw B, Rohm M
J Clin Invest
· 2026 May · PMID 42138073
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Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of ci...Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.
Wang Y, Huang H, Shao F
… +8 more, Eshwaran R, Qin M, Karim N, Ren Y, Dobreva G, Hammes HP, Wieland T, Feng Y
J Clin Invest
· 2026 May · PMID 42138072
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Diabetic retinopathy involves early retinal vascular barrier breakdown and pericyte loss, yet the initiating molecular events remain poorly defined. Vascular endothelial cadherin (VE-cadherin), a key regulator of endothe...Diabetic retinopathy involves early retinal vascular barrier breakdown and pericyte loss, yet the initiating molecular events remain poorly defined. Vascular endothelial cadherin (VE-cadherin), a key regulator of endothelial integrity, is notably reduced in diabetic and prediabetic nucleoside diphosphate kinase B-deficient (NDPKB-deficient) mouse retinas, particularly in the retinal deep capillary layer, and this decline precedes pericyte loss. In vitro, high glucose (HG) and NDPKB deficiency induced VE-cadherin Y685 phosphorylation, promoting its junctional internalization, activating the hexosamine biosynthesis pathway, and increasing angiopoietin 2 (Ang2), resulting in impaired endothelial barrier function and disrupting pericyte attachment. Preventing Y685 phosphorylation through VE-cadherin Y685F mutation blocked these HG- and NDPKB-driven pathological effects. Pharmacological intervention experiments identified protein O-linked β-N-acetyl glucosamine (O-GlcNAc) modification as a mediator of Y685-dependent Ang2 upregulation. In vivo, VE-cadherin Y685F-knockin mice were protected from diabetes- and prediabetes-induced vascular hyperpermeability, exhibited reduced protein O-GlcNAcylation and Ang2 induction, and maintained neuronal function. O-GlcNAc-enriched retinal proteomics further showed that the Y685F mutation restored balanced neurovascular and mitochondrial pathways. These findings highlight the potential of targeting VE-cadherin Y685 phosphorylation as a promising therapeutic approach to maintain retinal vascular integrity and attenuate the pathological progression of diabetic and prediabetic retinopathy.
Based on the observation that loss-of-function mutations of KMT2C and KMT2D (KMT2C/D) are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse model (GEMM) to conditionally knock out...Based on the observation that loss-of-function mutations of KMT2C and KMT2D (KMT2C/D) are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse model (GEMM) to conditionally knock out Kmt2c and Kmt2d in gastric epithelial cells. We observed that Kmt2c/d loss led to nuclear dysplasia, cellular crowding, and expansion of cells with mixed gastric lineage markers. When combined with Pten deletion, Kmt2c/d loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks post Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human intestinal type gastric adenocarcinoma. Bioinformatic integration of single cell RNA-seq of our GEMMs and human gastric cancer datasets shows co-clustering of normal and of cancerous gastric epithelial cells. Kmt2c/d knockout in gastric epithelium reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering the cells to be hypersensitive to mTORC1 inhibitors. Additionally, Kmt2c/d knockout increased MHC-I molecule expression and enhanced antigen presentation. Combination of mTORC1 inhibition and anti-PD1 immunotherapy markedly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of Kmt2c/d loss in gastric cancer initiation and suggest the potential therapeutic strategies for KMT2C/D-deficient gastric cancer.
Qu P, Ding S, Zhang Y
… +30 more, Zhao Y, Song E, Hu L, Ding R, Cao W, Hou Y, Qi J, Zhao J, Duan C, Liu S, Shen C, Zhao Y, Guo Y, Zheng Z, Luo S, Hu H, Bai L, Zhao S, Wang B, He S, Wu Y, Xiong X, Wu Q, Gu W, Rom O, Xu A, Zheng L, Zhang J, Liu E, Chen YE
J Clin Invest
· 2026 Jul · PMID 42118590
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The global prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising, driven by a complex interplay of metabolic disturbances, inflammation, and fibrosis, yet effective treatment options remain limi...The global prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising, driven by a complex interplay of metabolic disturbances, inflammation, and fibrosis, yet effective treatment options remain limited. This study examined the relationships among intestinal microbial dysbiosis, ammonia production, and hepatic CD8+ T cell activity in MASH, then assessed the therapeutic potential of DT-109, a glycine-based tripeptide. We investigated the gut/liver axis across human cohorts and both nonhuman primate and mouse MASH models. Multiomics approaches were used to characterize ileal microbiota, ammonia levels, and hepatic immune and metabolic pathways. Causality was verified through microbiota transplantation, C. perfringens NirA-knockout mutants, and functional validation in vitro and in vivo. The efficacy of DT-109 was evaluated in nonhuman primates and mice. Our results revealed a significant increase in the ammonia-producing gut bacterium C. perfringens, which led to elevated intestinal ammonia and disruption of the intestinal barrier in MASH. Elevated ammonia levels triggered FosB-mediated upregulation of CCL5 in CD8+ T cells, which in turn drove T cell cytotoxicity in the liver. Notably, DT-109 effectively lowered C. perfringens abundance, reduced intestinal ammonia, restored intestinal barrier integrity, and alleviated CD8+ T cell dysregulation in MASH. These results identify a distinct mechanism in which gut-derived ammonia drives CD8+ T cell-mediated MASH and demonstrate that DT-109 effectively targets this axis by inhibiting C. perfringens and reducing ammonia, ultimately ameliorating MASH.
Ma Y, Liu N, Li Y
… +34 more, Zhang D, He S, Lv J, Jiang Y, Jian G, Zhang J, Zhu P, Ma Y, Lin J, Li J, Wu T, Xu Y, Lyu X, Wang Y, Li Y, Niu YS, Guo Z, Lin C, Fang N, Jiang W, Wang L, Yuan M, Wang S, Huang S, Huang Q, Li J, Lu J, Chen B, Zhong G, Liu H, Ding F, Weng S, Li R, Zhang A
J Clin Invest
· 2026 Jul · PMID 42118587
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BACKGROUNDImmune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) significantly impairs cancer therapy and patient quality of life, yet its pathogenic mechanisms remain unclear.METHODSThrough integrated singl...BACKGROUNDImmune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) significantly impairs cancer therapy and patient quality of life, yet its pathogenic mechanisms remain unclear.METHODSThrough integrated single-cell multi-omics analysis of paired peripheral blood, synovial fluid, and tumor samples from longitudinal ICI-IA cohorts and matched controls, we identified a unique regulatory T-cell (Treg) population coexpressing CD137 and IL-6R (AtpTreg).RESULTSThese cells exhibited reduced immunosuppressive capacity while aberrantly producing high levels of IL-17 and promoting proinflammatory responses of synoviocytes. AtpTreg exhibits shared clonotypes and phenotypes across tissue compartments. Notably, AtpTreg frequency correlates with increased arthritis severity yet paradoxically associates with improved overall survival. Anti-IL6R therapy reduced AtpTreg levels, corresponding with improved arthritis outcomes and quality of life, without compromising anti-tumor immunity.CONCLUSIONOur findings define a pathogenic Treg subset in ICI-IA and validate IL-6R blockade as a mechanism-based therapeutic strategy, bridging mechanistic discovery to clinical translation.TRIAL REGISTRATIONNCT07357636.FUNDINGThe National Natural Science Foundation of China General Fund Project; National Natural Science Foundation of China Youth Science Fund Project; Regional joint key support project of National Natural Science Foundation of China; Natural Science Foundation of Fujian Province; Joint Funds for the Innovation of Science and Technology, Fujian Province.
Essel Dadzie H, Green YS, Camolotto SA
… +7 more, Arnold HU, Gumbleton M, Guo M, Mino-Kenudson M, Maeda Y, Spike BT, Snyder EL
J Clin Invest
· 2026 Jul · PMID 42118585
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Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary...Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary to gastric switch marked by aberrant activation of hepatocyte nuclear factor 4 alpha (HNF4α), a master regulator of gastrointestinal/hepatic differentiation. We show that HNF4α promoted IMA growth and activated a gastric pit cell-like program. Loss of HNF4α enabled forkhead box A1 and A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, nongastric identities in IMA. HNF4α also established a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhanced response to KRASG12D inhibition. Mechanistically, HNF4α blocked cell-cycle exit in drug-tolerant persister cells and promoted activity of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 activation partially rescued the effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhanced sensitivity to KRASG12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRASG12D inhibition in IMA.
Lee C, Grijalva RM, Tejwani L
… +7 more, Bae E, Chase A, Ro H, Kim H, Olmos V, Orengo JP, Lim J
J Clin Invest
· 2026 Jun · PMID 42113962
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Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease marked by progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1. While oligodendroglial dysfunct...Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease marked by progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1. While oligodendroglial dysfunction precedes PC loss, its direct contribution toward SCA1 pathogenesis remains unclear. Here, using an oligodendroglia-specific SCA1 conditional knockin mouse model, we demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation, ultimately impairing motor coordination. Transcriptomic analysis uncovers cerebellar oligodendrocyte subtypes with distinct gene expression signatures and aberrant abundance that contribute to demyelination. This, compounded by a progressive decline in the neuroprotective functions of a cerebellum-specific oligodendrocyte subtype, establishes a critical link between demyelination, axo-myelinic dysfunction, and axonal pathology in SCA1. Upstream transcriptional regulator analysis in oligodendroglia identifies transcription factor 7-like 2 (TCF7L2) and huntingtin (HTT) as key mediators of oligodendroglial dysfunction in SCA1, suggesting shared pathogenic mechanisms with other polyglutamine diseases. Collectively, these findings establish oligodendroglia as key mediators of SCA1 pathogenesis and underscore their critical role in preserving PC axonal integrity.
Zhang X, Liu X, Qiao Y
… +12 more, Rabata A, Liu N, Yao C, Parimon T, Chen D, Hogaboam C, Chen P, Stripp B, Gardell SJ, Jiang D, Noble PW, Liang J
J Clin Invest
· 2026 Jun · PMID 42096291
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Alveolar type 2 (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central reg...Alveolar type 2 (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central regulator of cellular energy metabolism. We have previously reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor cell function of IPF AT2 cells. In this study, we found that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), was significantly downregulated in IPF AT2 cells. NAMPT deficiency impaired AT2 renewal and enhanced lung fibrosis through downregulation of SIRT7 and SOD2, which resulted in increased oxidative stress, mitochondrial dysfunction, accumulated aberrant transitional cells, and impaired differentiation from AT2 to alveolar type 1 (AT1) cells. A mouse model with AT2-specific deletion of Nampt showed severely impaired AT2 renewal capacity and increased susceptibility to bleomycin lung injury. Activation of NAMPT by small-molecule activators promoted IPF AT2 renewal and reversed lung fibrosis in WT mice. NAMPT activation is a potentially promising therapeutic strategy for restoring AT2 progenitor cell function and halting or reversing progressive pulmonary fibrosis.
Ho WS, Mondal I, Liu J
… +10 more, Sun R, Huo J, Gao C, Das O, Tieu D, Sun J, Lin H, Zhang P, Yu J, Lu RO
J Clin Invest
· 2026 Jul · PMID 42085538
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Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current therapies are associated with substantial morbidity, and prognosis remains poor in high-risk subgroups, particularly those with TP53 mutati...Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current therapies are associated with substantial morbidity, and prognosis remains poor in high-risk subgroups, particularly those with TP53 mutations or relapsed disease. Cellular senescence is a tumor-suppressive program implicated in MB, but its role in antitumor immunity remains incompletely understood. We found that protein phosphatase 2A (PP2A) regulated immunogenic senescence in MB. Genetic ablation of the PP2A catalytic subunit PP2Ac or depletion of the regulatory subunit PP2A-B56α induced senescence in MB models. PP2Ac-deficient senescent cells exhibited increased MHC class I expression and enhanced immunogenicity. In syngeneic orthotopic models, PP2Ac loss prolonged survival in an immune- and CD8+ T cell-dependent manner. Analysis of patient datasets showed that senescence-associated gene signatures correlated with improved survival. Single-cell transcriptomic analysis further revealed that senescent MB cells were heterogeneous and that reduced PP2A activity was associated with an immunogenic senescence state. Because the PP2A inhibitor LB-100 has limited potency and off-target effects, we developed a lipid nanoparticle (LNP) platform to deliver siRNA targeting PPP2CA. LNP-small-interfering PP2Ac efficiently silenced PP2Ac in vitro and, when delivered locally in vivo, prolonged survival in a CD8+ T cell-dependent manner. Together, these findings identify PP2A as a regulator of immunogenic senescence in MB and support PP2Ac targeting as a therapeutic strategy.
Gay CL, Xu Y, Weideman AMK
… +28 more, Shaw FR, Kuruc JD, Conrad SZ, Mariano SA, Samir S, Kallon S, Sponaugle AT, Warren JA, Clutton GT, Abad-Fernandez M, Kapper C, Bradley AB, Baker CE, Pedersen SM, Moeser MJ, Burke L, Wee EG, Crook A, Laird GM, Cyktor JC, Mellors JW, Zhou S, Fox L, Eron JJ, Margolis DM, Hudgens MG, Hanke T, Goonetilleke N
J Clin Invest
· 2026 Jun · PMID 42084923
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BACKGROUNDApproaches to achieving antiretroviral therapy-free (ART-free) remission from HIV-1 must consider that people over 50 years now comprise the majority of people with HIV (PWH) on ART in various regions, includin...BACKGROUNDApproaches to achieving antiretroviral therapy-free (ART-free) remission from HIV-1 must consider that people over 50 years now comprise the majority of people with HIV (PWH) on ART in various regions, including the United States.METHODSWe report a double-blind, randomized trial in which PWH on ART, aged 21-60 years, received modified vaccinia Ankara-vectored (MVA-vectored) vaccines, MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4), either alone or in combination (n = 7/group), or saline placebo (n = 3). M3 and M4 contain complementary HIVconsvX immunogens that each span the same regions in HIV-1 Gag and Pol but differ by approximately 8% at the amino acid level.RESULTSM3, M4, and M3M4 regimens were well tolerated and all significantly increased both the frequency (peak median increase ~3-fold) and breadth of the HIVconsvX-specific T cell response while redirecting T cells to target conserved regions in HIV-1 for up to 10 weeks after vaccination. We also demonstrated that vaccination increased frequencies of T cells targeting participant autologous HIV-1 sequences. Vaccination mostly expanded preexisting HIV-1-specific T cells and did not impact CD4+ T cell activation, low-level viremia, or integrated HIV-1 provirus. Linear regression indicated that age was independently and negatively associated with the change in T cell frequency at 1, 2, and 10 weeks after vaccination (~1.41-fold decrease per 10 years older). After adjusting for age, years on ART was positively associated with HIVconsvX-specific T cell frequencies at 1 and 2 weeks following vaccination.CONCLUSIONIn PWH receiving ART, MVA.HIVconsvX vaccines significantly increased T cells targeting conserved regions of HIV-1. Novel strategies may be required to enhance anti-HIV-1 immunity in older adults.TRIAL REGISTRATIONClinicalTrials.gov NCT03844386FUNDINGNIH National Institute of Allergy and Infectious Diseases (NIAID) grants U01AI131310, HHSN272201100021I/HHSN27200037 (subcontract OX-14007.004.0037-212), UM1TR004406, P30AI050410, and P30CA016086; International AIDS Vaccine Initiative; European and Developing Countries Clinical Trials Partnership SRIA2015-1066; European Commission's Horizon 2020 Research and Innovation Programme 681137.