Top read articles in the last 30 days
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Abstract
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.
Authors
Pengxiang Qu, Shusi Ding, Yanru Zhang, Yang Zhao, Erfei Song, Liangshuo Hu, Ruike Ding, Wenbin Cao, Yiting Hou, Jia Qi, Juan Zhao, Chenjing Duan, Shuangqing Liu, Chong Shen, Ying Zhao, Yanhong Guo, Zuowen Zheng, Shiwei Luo, Huizhong Hu, Liang Bai, Sihai Zhao, Bo Wang, Shuixiang He, Yi Wu, Xuelian Xiong, Qiutong Wu, Weiwang Gu, Oren Rom, Aimin Xu, Lemin Zheng, Jifeng Zhang, Enqi Liu, Y. Eugene Chen
Total views: 4098
Abstract
Gene therapy–based biological pacemakers have been proposed as an alternative to their hardware-based counterparts. In this context, short-term ectopic expression of the T-box transcription factor 18 (TBX18) in the ventricle has been reported to generate potent, short-term pacemaker function in various animal models. Here, we investigated the impact of adeno-associated virus–mediated (AAV-mediated), long-term expression of TBX18 and compared the outcomes with those of the pacemaker ion channel hyperpolarization-activated cyclic nucleotide-gated potassium and sodium channel 2 (Hcn2). Our findings revealed that CMV-driven ectopic TBX18 expression in mouse hearts led to severe cardiac fibrosis. At lower, nonfibrogenic levels, TBX18 maintained its transcriptional function but failed to induce pacemaker phenotypes. TBX18-expressing cells showed suppressed expression of key working myocardial genes, but the pacemaker gene program was not induced. Electrophysiological studies showed abnormal automaticity in TBX18-expressing cells, combined with prolonged repolarization and various current changes. However, no hyperpolarization-activated funny current was detected. In a complete atrioventricular block rat model, AAV-mediated Hcn2 expression induced robust ectopic pacemaker activity in the presence of isoproterenol, whereas TBX18 expression neither generated such activity nor augmented Hcn2-mediated pacing. In conclusion, at functionally nonfibrogenic levels, TBX18 is neither sufficient nor necessary to induce pacemaker activity. In contrast, Hcn2 generates reliable pacing, making it a more viable candidate for biological pacemaker development.
Authors
Jianan Wang, Mathilde R. Rivaud, Mischa Klerk, Arie R. Boender, Ruud N. Visser, Rinske Sparrius, Hee Young Lee, Karel van Duijvenboden, Huiling Zhou, Yuting Yang, Emiel J.M. Kramer, Kyung Ho Park, Larry C. Park, Silke Schrödel, Christian Thirion, Eric Ehrke-Schulz, Anja Ehrhardt, Osne F. Kirzner, Klaus Neef, Hanno L. Tan, Arie O. Verkerk, Vincent M. Christoffels, Gerard J.J. Boink
Total views: 3384
Abstract
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.
Authors
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
Total views: 3047
Abstract
BACKGROUND Immune checkpoint inhibitor–induced inflammatory arthritis (ICI-IA) significantly impairs cancer therapy and patient quality of life, yet its pathogenic mechanisms remain unclear.METHODS Through 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).RESULTS These 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.CONCLUSION Our 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 REGISTRATION NCT07357636.FUNDING The 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.
Authors
Yifei Ma, Nianqi Liu, Yan Li, Denghan Zhang, Shaohui He, Jun Lv, Yongluo Jiang, Guangmin Jian, Jingyao Zhang, Pengfei Zhu, Yue Ma, Jiacai Lin, Jin Li, Tong Wu, Yiwei Xu, Xiajie Lyu, Youlong Wang, Yiming Li, Yu Si Niu, Zhenyun Guo, Churong Lin, Ningnan Fang, Wei Jiang, Lihong Wang, Mengqin Yuan, Shenyue Wang, Shulin Huang, Qi Huang, Jinjian Li, Jun Lu, Bocen Chen, Guanqing Zhong, Haizhou Liu, Fadian Ding, Shangeng Weng, Rui Li, Ao Zhang
Total views: 2941
Abstract
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.
Authors
Winson S. Ho, Isha Mondal, Jingjing Liu, Raymond Sun, Jiawei Huo, Chao Gao, Oishika Das, Daren Tieu, Jingqi Sun, Hanchen Lin, Peng Zhang, Jiyang Yu, Rongze Olivia Lu
Total views: 2931
Abstract
BACKGROUND Minimally invasive biomarkers predicting the immunotherapy response in head and neck squamous cell carcinoma (HNSCC) remain an unmet clinical need.METHODS In a prospective, multi-institutional phase II trial, we performed whole-genome sequencing of 185 longitudinal plasma cell-free DNA (cfDNA) samples from 68 patients with locally advanced, surgically resectable HNSCC who received neoadjuvant and adjuvant pembrolizumab. We developed the regional motif diversity score (rMDS), a fragmentomic metric that quantifies the entropy of cfDNA 5′-end motifs across genomic regions.RESULTS Unsupervised analysis showed that rMDS robustly distinguished responders from nonresponders, outperforming established fragmentomic metrics and copy number alterations while remaining independent of technical confounders. Longitudinal rMDS changes localized to regions enriched for immune-, lectin-, and keratinization-related genes — hallmarks of squamous cell carcinoma — reflecting tumor–peripheral immunity interplay during treatment. The most dynamic regions clustered at telomere-proximal loci, suggesting a link between telomere biology and cfDNA fragmentation. An rMDS-based machine learning classifier achieved AUC 0.89–0.99 across validation settings, with the highest accuracy after treatment, outperforming PD-L1 expression and tumor fraction in matched samples. Predicted responders showed improved disease-free survival (log-rank P = 0.035; HR 2.67, 95% CI 1.03–6.92).CONCLUSION rMDS represents a biologically meaningful and clinically actionable biomarker for the immunotherapy response in HNSCC, and merits integration into future risk assessment frameworks.TRIAL REGISTRATION ClinicalTrials.gov NCT02641093.FUNDING National Human Genome Research Institute (NHGRI), NIH grant R56HG012360; startup funds from Cincinnati Children’s Hospital Medical Center, Northwestern University, and Robert H. Lurie Comprehensive Cancer Center; Science Olympiad Alumni Research Grant, Science Olympiad USA Foundation; Merck Sharp & Dohme Corp.
Authors
Ravi Bandaru, Hailu Fu, Haizi Zheng, Jocelyn Liang, Li Wang, Shuchi Gulati, Benjamin H. Hinrichs, Mingxiang Teng, Bin Zhang, Masha Kocherginsky, De-Chen Lin, David A. Hildeman, Francis P. Worden, Matthew Old, Neal E. Dunlap, John M. Kaczmar, Maura L. Gillison, Dalia El-Gamal, Trisha Wise Draper, Yaping Liu
Total views: 2833
Abstract
BACKGROUND Anti-nephrin autoantibodies have emerged as a putative pathogenic driver in a subset of patients with podocytopathies, including those with posttransplant disease recurrence.METHODS We measured anti-nephrin autoantibodies in a cohort of 65 patients with podocytopathy associated with steroid-sensitive nephrotic syndrome (n = 39) and steroid-resistant nephrotic syndrome (n = 26) and in 34 patients with posttransplant podocytopathy recurrence. Fourteen patients with membranous nephropathy and 20 healthy volunteers served as controls. ELISA and immunoprecipitation assays were performed to detect anti-nephrin IgG using 2 different recombinant human nephrin proteins. Immunofluorescence analysis was performed to assess gG deposition and its colocalization with nephrin in renal biopsies.RESULTS When using an ELISA based on murine cell-derived human antigen, the highest positivity was found in healthy volunteers (55%), correlating with levels of circulating natural anti–α-galactose-α-1,3-galactose antibodies. This cross-reactivity was abrogated with recombinant human nephrin expressed in human cells. In this setting, very low prevalence (<5%) of anti-nephrin antibody-positive patients was found in steroid-sensitive and -resistant nephrotic syndrome cohorts and in patients with posttransplant disease recurrence. These frequencies were comparable to healthy volunteers. Using confocal and super-resolution microscopy, only trace amounts of IgM, but no IgG, were found in the glomeruli of analyzed biopsies, which did not colocalize with nephrin.CONCLUSION With the methodology presented here, anti-nephrin reactivity was extremely rare and occurred at comparably low frequencies in healthy controls, native-kidney podocytopathies, and posttransplant disease recurrence. This suggests that these autoantibodies are not inherently disease specific and may not serve as a broad biomarker across podocytopathies.TRIAL REGISTRATION ClinicalTrials.gov NCT06334692.FUNDING The Medici di Marignano family.
Authors
Francesco Pecoraro, Luca Perico, Federica Casiraghi, Paola Rizzo, Matias Trillini, Andrea Angeletti, Manuel Alfredo Podestà, Xhuliana Kajana, Agnese Spennacchio, Marta Todeschini, Marilena Mister, Giuseppe Castellano, Ariela Benigni, Giuseppe Remuzzi
Total views: 2717
Abstract
We previously identified a muscular dystrophy caused by biallelic variants in JAGGED2 (JAG2), whose protein product, JAG2, is a canonical NOTCH ligand. However, the disease mechanism remains unclear, particularly with respect to muscle stem cell (muscle satellite cell/MuSC) function and muscle regeneration. We examined the consequences of JAG2 deficiency and modeled pathogenic JAG2 variants in vitro and in vivo, the latter in mouse and fly models and with particular attention to the MuSC–muscle endothelial cell (MuEC) niche. We found that both Jag2 deficiency and overexpression of pathogenic JAG2 variants impaired NOTCH signaling and myogenic self-renewal and differentiation. Hypomorphic Jag2 mutant (Jag2sm) mice displayed depleted MuSCs, corresponding with impaired muscle regeneration in those mice. Coculture experiments and the examination of cell type–specific Jag2 conditional knockout mice demonstrated that MuEC-specific Jag2 knockout resulted in reduced MuSC self-renewal, while MuSC-specific Jag2 knockout resulted in reduced myogenic differentiation. Human reference JAG2, but not human pathogenic variants of JAG2, rescued the deficiency of Serrate, the Drosophila ortholog of JAG2. Therefore, pathogenic variants in JAG2 impair muscle development and regeneration through disrupted cell-autonomous cis-inhibition and nonautonomous trans-activation involving NOTCH signaling dysfunction. Our findings indicate that optimizing JAG2-mediated NOTCH signaling is a potential therapeutic approach for JAG2-related muscular dystrophy.
Authors
Minoru Tanaka, Nam Chul Kim, Isabelle Draper, Hannah R. Littel, Mekala Gunasekaran, Johnnie Turner, Natalya M. Wells, Qasim Mujteba, Yoko Asakura, Peter B. Kang, Atsushi Asakura
Total views: 2622
Abstract
MDM2 is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53 activation induces MDM2 transcription, creating a feedback loop that blunts inhibitor efficacy. We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling. In vivo, KT-253 produced deep and durable tumor regressions, including complete responses in patient-derived xenograft models. Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.
Authors
Varsha Ananthapadmanabhan, Simone Bruno, Leonard Vonk, Yu-Chen Cheng, Abeba Teshager, Benjamin K. Eschle, Charles L. Howarth, Joana S. Rodrigues, Julia Schnabel, Ananya Kodali, Prafulla C. Gokhale, Rujuta Kshirsagar, Susanne B. Breitkopf, Kirti Sharma, Joao A. Paulo, Yvonne Li, Andrew D. Cherniack, Franziska Michor, Yogesh Chutake, Joyoti Dey, James A. DeCaprio
Total views: 2590
Abstract
Tregs expressing forkhead box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg identity and suppressive function upon activation. Here, we demonstrate that the H3K27 lysine demethylase KDM6B, which catalyzes the opposing reaction to EZH2, is also required for Treg identity and function after activation. Treg-specific deletion of Kdm6b impaired tissue Treg fate and function. KDM6B was upregulated after T cell antigen receptor signaling in Tregs and contributed to the regulation of Treg-associated gene expression through both direct and indirect mechanisms. A subset of Treg functional genes were direct targets of KDM6B and were co-occupied by FOXP3 at cis-regulatory regions, where KDM6B recruitment limited H3K27me3 accumulation. More broadly, KDM6B-dependent H3K27 demethylation facilitated Treg gene expression programs that supported tissue Treg homeostasis.
Authors
Minghong He, Beisi Xu, Pria G. Bose, Morgan J. McCullough, Rani S. Sellers, Xinying Zong, Wenjie Qi, Brianna L. Banten, Miriya K. Tune, Matthew P. Zimmerman, Genevieve Mullins, Brian C. Miller, J. Justin Milner, Jason K. Whitmire, Ageliki Tsagaratou, Karl B. Shpargel, Claire M. Doerschuk, Yong-Dong Wang, Jacob A. Steele, Shondra M. Pruett-Miller, Yongqiang Feng, Jason R. Mock
Total views: 2516
Abstract
Polycystic ovary syndrome (PCOS), also known as polyendocrine metabolic ovarian syndrome (PMOS), is the most common endocrinologic disorder to affect women. Despite this, the pathophysiology of the disease is not entirely known. This has hindered the diagnosis of the disease and appropriate treatment for millions of individuals. In this Review, we discuss the proposed pathophysiology of PCOS from a translational perspective. We review the existing diagnostic criteria of PCOS and current management strategies. Finally, we discuss the long-term health sequelae associated with PCOS, future directions, and areas of needed research in this often-overlooked disease.
Authors
Jessica L. Chan, Irene Masini, Margareta D. Pisarska
Total views: 8455
Abstract
The reality of an aging population demands a deeper understanding of aging as a biological process, rather than as a chronological descriptor. Chronological age poorly captures interindividual heterogeneity in physiological and functional decline, disease susceptibility, and mortality risk. In contrast, biological age encompasses deterioration at the molecular, cellular, tissue, organ, functional, and organismal levels and provides insight into why two individuals with the same chronological age exhibit differences in physiological function, disease susceptibility, and mortality risk. While early models of biological age relied on functional markers or composite scores derived largely from longitudinal cohort studies, more recent models integrate molecular profiling with machine learning to ascertain biological aging trajectories. In parallel, new artificial intelligence tools have been applied to various imaging modalities and other forms of complex data to elucidate latent patterns and estimate biological age. In this state-of-the-art Review, we explore historical and modern approaches to estimating biological age and highlight key conceptual, technical, and translational challenges that remain unresolved. As geroscience-guided interventions are incorporated into clinical evaluations, robust and accurate interpretable measures of biological aging are crucial to ascertain treatment effects in clinical trials.
Authors
Baljash S. Cheema, Bedirhan Boztepe, Moses O. Awofolaju, Mallory S. Hubbard, William B. Marcus, Frank J. Palella, Mohamed Abdel-Mohsen, David M. Liebovitz, Manjot K. Gill, R. James Cotton, John T. Wilkins, Douglas E. Vaughan
Total views: 7747
Abstract
GLP-1 receptor agonist (GLP-1RA) medications have transformed the treatment of type 2 diabetes (T2D) and obesity, with robust evidence for cardiovascular and renal benefits. Nevertheless, GLP-1RA therapy is associated with a pattern of adverse events affecting their safety and tolerability. Here, we delineate mechanisms potentially leading to adverse responses to GLP-1RAs, describe the impact of side effects on treatment persistence, discuss potential mitigation strategies, and identify areas requiring further studies. Concerns that GLP-1RAs raise the risk for acute pancreatitis and pancreatic cancer have been dispelled by long-term clinical trials. However, GLP-1RAs may confer an increased risk for thyroid cancer. Sight-threatening eye complications resulting from rapid reductions in glycemia may be avoided by retinal screening and ophthalmologic treatment before GLP-1RA initiation. The slowing of gastric emptying with GLP-1RA treatment increases the propensity for retained gastric contents, which could increase the risk of aspiration during upper gastrointestinal endoscopy or general anesthesia. These risks may, however, be elevated in individuals with long-standing T2D even in the absence of GLP-1RA treatment. Improved pharmacovigilance and a more standardized, quantitative assessment of adverse events in clinical trials, particularly in the assessment of gastrointestinal symptoms, would facilitate definition of the benefit-risk relationship for individual medications and indications.
Authors
Ryan J. Jalleh, Nicholas J. Talley, Michael Horowitz, Michael A. Nauck
Total views: 5176
Abstract
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed as a uniformly beneficial antiviral and antitumor signaling axis, emerging evidence reveals that cGAS-STING functions as a context-dependent immune rheostat whose impact is dictated by signal magnitude, timing, cellular origin, subcellular localization of signaling components, and tissue context. These parameters explain why pathway activation can promote tumor rejection, vaccine efficacy, and host defense in some settings yet drive immune suppression, metastasis, neuroinflammation, or autoinflammatory disease in others. In this Review, we synthesize mechanistic and clinical insights across agonist and antagonist strategies targeting the cGAS-STING pathway in cancer, infectious disease, neurodegeneration, and interferonopathies. We highlight why first-generation STING agonists have underperformed clinically and how next-generation delivery systems and cGAS-directed approaches may overcome these limitations. We propose a disease-centric framework that integrates spatial delivery, dosing architecture, and pharmacodynamic biomarker discovery to enable rational modulation of cGAS-STING, repositioning the pathway as a tunable immunologic control node for precision therapy rather than a binary on/off switch.
Authors
Akanksha S. Mahajan, Connor M. Forsyth, Cao Dai Phung, Xinhe Shen, Rachel Jarvis, Alexander H. Stegh
Total views: 3830
Abstract
As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.
Authors
Cornelia M. Weyand, Jörg J. Goronzy
Total views: 3610
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide, highlighting the need for novel therapeutic approaches. Inflammation plays a key role in CVD pathogenesis, and accumulating evidence has implicated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway in this process. The cGAS/STING pathway recognizes both non-self- and self-DNA, including mitochondrial and nuclear DNA, to activate its downstream proinflammatory signaling molecules, including TANK-binding kinase 1, IFN regulatory factor 3, and NF-κB. Various pathological stressors have been shown to induce self-DNA release into the cytosol and bloodstream from damaged cells in the cardiovascular system, indicating that circulating cell-free DNA is a useful biomarker of CVDs; however, how this contributes to the inflammatory signaling, cell death, and fibrosis that characterize CVDs remains unclear. Here, we discuss the current understanding on the roles of self-DNA and the cGAS/STING pathway in the pathophysiology of CVDs and the therapeutic potential of targeting this pathway.
Authors
Wataru Saitoh, Yasutomi Higashikuni, Oyunbileg Bavuu, Masataka Sata, Daiju Fukuda
Total views: 3576
Abstract
The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriate or sustained activation of this pathway can drive chronic inflammation, autoimmunity, and disease-associated immune dysfunction, which can promote cancer growth. Effective immunity therefore depends on precise regulatory control that restrains cGAS/STING activity under homeostatic conditions while preserving the capacity for swift and robust responses to diverse danger signals. In this Review, we synthesize emerging principles that regulate cGAS/STING signaling across cellular contexts to control signal initiation, amplification, and termination. We discuss how disruption, persistence, or pathological rewiring of these regulatory processes contributes to immune imbalance across health and disease, promoting chronic inflammation, immunosuppression, and tissue pathology, with particular relevance to tumor progression and therapeutic resistance. Finally, we consider how restoring appropriate cGAS/STING regulation, rather than simply enhancing or inhibiting pathway activity, may reestablish immune homeostasis and improve therapeutic outcomes in cancer and other inflammatory diseases, framing the pathway as a dynamic regulatory circuit rather than a simple linear signaling cascade.
Authors
Min-Guk Cho, Rachel Lee, Jaycee Johnson, Gaorav P. Gupta
Total views: 3382
Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) reduce rates of cardiovascular and chronic kidney disease in people with type 2 diabetes and/or obesity, with ongoing clinical trials investigating their effects in people with metabolic liver disease, arthritis, and both substance use and neurodegenerative disorders. Acute and chronic activation of GLP-1 receptor signaling also reduces systemic and tissue inflammation in mice and humans, through weight loss–dependent and –independent mechanisms, actions that may contribute to the expanding spectrum of clinical benefits ascribed to GLP-1 medicines. In this Review, we highlight current understanding of the direct and indirect antiinflammatory effects and mechanisms of GLP-1 medicines in both preclinical and clinical studies, covering emerging concepts, clinical relevance, and areas of uncertainty that require further investigation.
Authors
Chi Kin Wong, Daniel J. Drucker
Total views: 3003
Abstract
Historically, antiobesity medications have been modestly effective at best, with side-effect profiles that limit compliance and often preclude the long-term therapy required to maintain weight loss. Recently developed therapies based on analogs of the gut hormone glucagon-like peptide-1 (GLP-1) have transformed the medical management of obesity, leading both to a degree of weight loss that rivals bariatric surgery and a reduction in morbidity and mortality associated with obesity-related complications. GLP-1 receptor agonist (GLP-1RA) therapies were developed to mimic the peripheral effects of GLP-1, but it is now well established that their efficacy in the treatment of obesity depends on reducing energy intake through their action in the central nervous system (CNS). Recent data indicate that the aversive gastrointestinal side effects of GLP-1RAs are also CNS mediated. Although a complete understanding of the neural circuits underlying GLP-1RA–induced weight loss remains elusive, a great deal has been learned in recent years. This Review summarizes proposed gut-brain and central mechanisms through which GLP-1 and its synthetic analogs regulate food intake and bodyweight.
Authors
Lisa R. Beutler
Total views: 2477
Abstract
Cancer diagnoses are prevalent in people with obesity and type 2 diabetes, and abundant clinical evidence supports the protective effects of weight loss for cancer prevention. Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized obesity and type 2 diabetes medicine and alleviate many comorbidities of these metabolic diseases. In this Review, we summarize the current clinical evidence for GLP-1 receptor agonists and cancer risk, including thyroid, pancreatic, gastrointestinal, and hormone-dependent malignancies. With few exceptions, recent meta-analyses report that GLP-1 receptor therapies do not increase cancer incidence and may lower risk in some cases. Preclinical studies reinforce the anticancer effects of GLP-1 receptor therapies, even in non-obese models. However, there are still many opportunities for translational insight as the field grows. Immune-modulating effects of GLP-1 receptor agonists are reported in several preclinical cancer studies, which may reflect direct action on immune cells or result from improved metabolic function. We highlight ongoing clinical trials for GLP-1 receptor therapies in cancer patients, and offer considerations for preclinical studies, including perspectives on the timing and duration of GLP-1 receptor agonist treatment, concurrent use of standard anticancer therapies, and interpretation of models of cancer risk versus progression.
Authors
Estefania Valencia-Rincón, Rajani Rai, Vishal Chandra, Elizabeth A. Wellberg
Total views: 2198
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)