Issue published September 15, 2026 Previous issue
- Volume 136, Issue 18
On the cover:
Basement membrane remodeling drives cyst formation in autosomal dominant polycystic kidney disease
Mazloum et al. report that polycystin-1 and the primary cilium govern the composition, mechanics, and shape of the tubular basement membrane, and that remodeling of this matrix initiates tubule dilation in autosomal dominant polycystic kidney disease. The cover image is a false-colored transmission electron micrograph of the thinned tubular basement membrane separating two polycystin-1–deficient tubular cells.
Mazloum et al. report that polycystin-1 and the primary cilium govern the composition, mechanics, and shape of the tubular basement membrane, and that remodeling of this matrix initiates tubule dilation in autosomal dominant polycystic kidney disease. The cover image is a false-colored transmission electron micrograph of the thinned tubular basement membrane separating two polycystin-1–deficient tubular cells.
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Reviews
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Abstract
Ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation and redox imbalance. Since its formal recognition in 2012, ferroptosis has emerged as a central pathway linking metabolic stress and oxidative injury to both physiologic and pathologic processes. Its functions extend from tissue sculpting during embryogenesis and tumor suppression to pathologic contributions in neurodegeneration, cardiovascular disease, liver and kidney injury, cancer, and inflammatory disorders. Despite these advances in our understanding of ferroptosis, critical questions remain regarding its precise regulation, context-specific consequences, and interactions with other cell death pathways. Continued progress in identifying biomarkers, defining context-specific roles, and developing selective modulators will be essential to translate ferroptosis biology into clinical therapies with broad impact. Here, we describe the current state of our understanding of the role of ferroptosis in physiology and its potential as a target mechanism in heart and kidney disease.
Authors
Simar J. Singh, Baljash Cheema, Hossein Ardehali
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Rare monogenic subtypes of migraine with aura, which include an autosomal dominant form of hemiplegic migraine (HM), are caused by exonic mutations whose functional consequences can be studied in cellular and animal models of the disease. This allows investigation of the neurobiological mechanisms at the molecular, cellular, and circuit level. Here, I review current knowledge of the genetics and pathophysiology of HM. After considering the genes whose mutations cause familial HM (FHM) and discussing how the encoded proteins are affected by the mutations, I consider the mouse models generated by introducing human FHM mutations in the orthologous genes, Cana1a, Atp1a2, and Scna1a. I discuss their phenotypes, highlighting their shared increased susceptibility to experimentally induced cortical spreading depression (CSD, the phenomenon which underlies migraine aura and may trigger the headache mechanisms) and migraine-relevant pain behaviors. I examine the alterations in the cerebral cortex and the mechanisms underlying the facilitation of CSD in the mouse models as well as the alterations in the trigeminovascular pain pathway and their possible contributions to migraine-relevant pain phenotypes. Finally, I discuss the translational implications of the pathogenic mechanisms of CSD facilitation.
Authors
Daniela Pietrobon
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Commentaries
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Going to the source: pancreatic lymph nodes maintain stem-like CD8+ T cells in human type 1 diabetes
Abstract
Where does autoimmune persistence reside in type 1 diabetes (T1D)? Detailed investigation of the pancreas and pancreatic lymph nodes (PLNs) may provide more definitive answers, yet most studies in these target tissues have been confined to mouse models. In nonobese diabetic (NOD) mice, disease development is prevented by PLN ablation, and these LNs harbor a stem-like population of autoreactive CD8+ T cells. In this issue, Peters et al. identified stem-like CD8+ T cell populations enriched in PLNs from humans with T1D and provide evidence for a developmental continuum linking lymphoid and pancreatic immune compartments. Their findings extend concepts previously established in NOD mice and in cancer immunology to humans with T1D, wherein self-renewing T cell populations sustain long-term immune responses. While the precise relationship between these stem-like cells and pathogenic autoreactive clones remains unresolved, this work positions the PLN as a potential reservoir of autoimmune persistence in T1D and a target for immune intervention.
Authors
Fatoumata Samassa, Sylvaine You, Roberto Mallone
×Abstract
Polyendocrine metabolic ovarian syndrome (PMOS) affects one of every eight women worldwide and is associated with high rates of cardiovascular disease, type 2 diabetes, and infertility. Polycystic ovarian syndrome (PCOS), another term for this condition, reflects a historical focus on its effects on the female reproductive system. Recently, however, experts and patient groups have advocated renaming the condition PMOS, conveying increasing recognition that hyperandrogenism and insulin resistance contribute to its pathology. In this issue, Nguyen et al. took a systems genetic approach that combined data from murine models of PMOS and data from human studies, identifying the splicing factor 3b subunit 1 (SF3B1) and IGFBP2, both previously associated with metabolic disease, as molecular drivers of PMOS. SF3B1 inhibitors improved PMOS symptoms in mice, including decreased adiposity, hypoandrogenism, and insulin levels. These findings open therapeutic and mechanistic avenues in the study of PMOS, including exploration of splice variants as regulators of disease progression.
Authors
Michaela M. Morhaus, Lauren W. Yowelunh McLester-Davis, Judith A. Simcox
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Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2, is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI, Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.
Authors
Caroline R. Sussman, Peter C. Harris
×Abstract
Multiple myeloma is a systemic and spatially heterogeneous cancer of plasma cells. Available methods for diagnosing and monitoring disease do not fully capture its heterogeneity. For instance, bone marrow sampling is anatomically limited and [18F]FDG PET/CT reflects glucose metabolism rather than a specific target. In this issue of JCI, Gu et al. reported a prospective phase I study of [68Ga]Ga-PFBC01, a nanobody tracer targeting B cell maturation antigen (BCMA). The study presents a coherent translational pathway for [68Ga]Ga-PFBC01 PET and demonstrates high sensitivity, associations with tissue and circulating disease measures, and clinical management impact. By shifting myeloma imaging from metabolic assessment toward target biology, [68Ga]Ga-PFBC01 PET may visualize whole-body disease distribution and actionable target expression, while blood-pool activity may reflect systemic antigen biology (Figure 1).
Authors
Yangmeihui Song, Wenyu Song, Weibo Cai
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Research Letter
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Abstract
Authors
S. Marina Casalino-Matsuda, Vijeeth Guggilla, Catherine A. Gao, Kaitlyn E. DeMeulenaere, Luisa Cusick, Samuel W. Fenske, Zhan Yu, Ziyan Lu, Suchitra Swaminathan, Rogan A. Grant, Maxwell J. Schleck, Murali Prakriya, Sudarshan Hebbar, Kenneth Stauderman, Helen K. Donnelly, Chiagozie I. Pickens, Luisa Morales-Nebreda, Richard G. Wunderink, Alexander V. Misharin, Benjamin D. Singer, G.R. Scott Budinger
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Research Articles
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Abstract
Human carcinomas often gain aggressive characteristics and escape cell type–specific treatment regimens through cryptic shifts in lineage states. However, the underlying mechanisms that govern lineage plasticity in carcinomas are undefined. Here in this study, we found that PAX5, a neural/lymphatic transcription factor, contributed to neuroendocrine (NE) lineage transition. PAX5 was highly expressed in aggressive human NE carcinoma cells and tissues but not in non-NE cancer cells and tissues. Deletion of Pax5 in Rb1fl/fl Trp53fl/fl mice caused a reduction of tumor vessels, loss of NE morphologic features, and decreased expression of ASCL1, NCAM, and SYP, whereas ectopic expression of PAX5 in CC10-rtTA TetO-hEGFRex19del/T790M mouse adenocarcinomas and in LNCAP prostate cancer xenografts induced an angiogenic microenvironment and NE morphology. Importantly, antiangiogenic drugs reduced NE features of Rb1fl/fl Trp53fl/fl tumors and blocked PAX5-induced NE transformation. These studies demonstrate an essential role of an angiogenic microenvironment in transition/maintenance of NE lineage, suggesting that targeting PAX5 and its downstream signaling may modulate lineage transitions responsible for treatment failure in both small cell neuroendocrine carcinoma and adenocarcinomas.
Authors
Ailing Wu, Yujie Hao, Xuemiao Yan, Junrong Liu, Lin Wang, Yan Jin, Wenxu Liu, Xiyue Chen, Yuan Jiang, Luc Girard, Zhiqun Shang, Jun Yan, Zhenfa Zhang, Wenchen Gong, Yuanjie Niu, Benjamin J. Drapkin, John D. Minna, Lance S. Terada, Zhenyi Ma, Zhe Liu
×Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global health concern. Nevertheless, its underlying pathological mechanisms remain poorly understood. Here, we showed that E3 ubiquitin ligase RING finger protein 10 (RNF10) protein levels were positively correlated with MASLD in both mice and humans. Hepatocyte-specific Rnf10 deletion attenuated liver steatosis, inflammation, and fibrosis. Conversely, adeno-associated virus–mediated hepatocyte-specific Rnf10 overexpression exacerbated MASLD-related phenotypes. Mechanistically, RNF10 interacted with carnitine palmitoyltransferase 1A and facilitated its degradation through K48-linked ubiquitination, thereby inhibiting fatty acid oxidation, promoting hepatic lipid accumulation, and ultimately exacerbating liver inflammation and fibrosis. Moreover, we utilized triantennary N-acetylgalactosamine to deliver siRNA specifically targeting Rnf10 to hepatocytes. This approach effectively ameliorated diet-induced liver steatosis, inflammation, and fibrosis in mice. Therefore, interfering with the expression or function of RNF10 may be a promising therapeutic strategy for MASLD.
Authors
Chunyuan Du, Yinliang Zhang, Hongkai Chang, Chaofan Xu, Sufang Sheng, Ke Xu, Wei Qiao, Yanjun Liu, Tongtong Zhang, Yong Gao, Peng Li, Yongsheng Chang
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Effector CD8+ T cells are key drivers of type 1 diabetes (T1D) pathogenesis, yet questions remain regarding the molecular defects leading to altered cytotoxicity, peripheral tissue phenotype, and receptor specificity. We analyzed human pancreatic lymph nodes (pLNs) using mass cytometry and single-cell RNA-seq (scRNA-seq) with combined T cell receptor (TCR) profiling. Cytometric analysis revealed enrichment of T stem cell memory–like (TSCM-like) cells (CD8+CD45RA+CD27+CD28+CCR7+CXCR3+) in T1D pLNs. scRNA-seq indicated an elevated inflammatory cytokine gene signature (IFITM3, LTB) along with regulators of terminal differentiation (BCL6, BCL3), coupled with downregulation of exhaustion-associated genes (DUSP2, NR4A2, TSC22D3) in CD8+ T cells in T1D pLNs. Immune response enrichment analysis (IREA) indicated IL-15 signaling as a significant driver of these phenotypes. Integrated TCR and transcriptomics analysis revealed a cluster of diverse naive-like CD8+ T cell clones in T1D pLNs. Comparison of pLNs and pancreatic tissue slice isolates indicated sharing of effector CD8+ T cells, with enhanced terminal effector signatures within the pancreas relative to paired pLNs. Multiplex imaging revealed differential localization of T cell factor 1 (TCF1)- and thymocyte selection-associated high mobility group box protein (TOX)-expressing T cells in the pancreas, with islet-proximal TCF1+TOX+ cells displaying a mixture of activation and exhaustion-associated phenotypes. Thus, we provide multimodal cellular profiles enriched in T1D tissues for consideration in therapeutic targeting.
Authors
Leeana D. Peters, Howard R. Seay, Justin A. Smith, Amanda L. Posgai, Reed L. Berkowitz, Clive H. Wasserfall, Mark A. Atkinson, Rhonda Bacher, Maigan A. Brusko, Todd M. Brusko
×Abstract
Cockayne syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in transcription-coupled nucleotide excision repair. Currently, no therapies are available for these patients. Adeno-associated virus–mediated (AAV-mediated) gene therapy offers an opportunity to address this unmet need. We designed an AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventricular injection in the Csa–/– Xpa–/– mouse model. Treatment with AAV9-CSA resulted in a significant increase in life span, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for clinical translation of an AAV gene therapy for patients with CS into humans.
Authors
Ana Rita Batista, Aine C. Scholand, William S. Callahan, McKenna K. Watson, Cassandra M. Sion, Tyler Mola, Kennedy O’Hara, Simon A. Wentworth, William S. Sena-Esteves, Oliver D. King, Robert M. King, Miguel Sena-Esteves
×Abstract
Autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of kidney failure, results from loss-of-function mutations in PKD1, encoding polycystin-1 (PC1). PC1 localizes to the primary cilium. In the absence of PC1, adverse signaling from the primary cilium orchestrates cyst formation, but the biomechanical underpinnings of this cilia-dependent cyst activation (CDCA) remain unclear. Combining tubule-specific orthologous mouse models with a tubule-on-chip platform, we show that PC1 and cilia govern the composition, mechanical properties, and shape of the tubular basement membrane (TBM), the principal rigid determinant of tubule geometry. PC1 loss triggered TBM thinning, heparan sulfate enrichment, and deformation, leading to distension, preferentially of the distal nephron. These changes were driven by a cilia-dependent transcriptional program, with GLIS2 — a key CDCA effector — participating as a downstream mediator. Reduction of TBM stiffness amplified Pkd1–/– tubule-on-chip dilation and increased cyst formation in vivo. Conversely, increasing luminal pressure through ureteral obstruction induced disproportionate distension of Pkd1-deficient tubules and triggered an irreversible cystogenic program. Together, these findings establish a TBM-centered biomechanical model of ADPKD in which tubule deformation is governed by both basolateral and luminal mechanical factors and identify the cilium/TBM axis, operating in part through GLIS2, as a central driver of cystogenesis.
Authors
Manal Mazloum, Brice Lapin, Rushdi Alghamdi, Jessica Vandensteen, Martine Burtin, Pascal Houillier, Lydie Cheval, Gilles Crambert, Vicky Scata, Camille Cohen, Christoph Schell, Michael Rehman, Amandine Aka, Karim Ourahmoun, Rui Benedito, E. Wolfgang Kuehn, Stéphanie Descroix, Tilman Busch, Michael Köttgen, Serge Garbay, Marie-Christine Verpont, Ellie Tang, Brigitte Lelongt, Nicolas Cagnard, Stefan Somlo, Sylvie Coscoy, Fabiola Terzi, Amandine Viau, Frank Bienaimé
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Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovered conserved genetic and environmental factors underlying PMOS, identified susceptible cell types and organs, and elucidated mechanisms linking PMOS to subsequent pathologies. For instance, we showed that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary–heart signaling circuits modulate cardiac function with aging. We further identified ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin, and glucose levels as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.
Authors
Christy M. Nguyen, Leandro M. Velez, Youngseo Cheon, Cimone L. Jackson, Casey D. Johnson, Ian Tamburini, Mingqi Zhou, Erik Alvstad, Isoo Yoon, Farheen Dustagheer, Marie Li, Tvisha Gujjarlapudi, Kaitlene Ofilan, Neha Mishra, Evan G. Williams, Danica Kwan, Carlos H. Viesi, Naveena Ujagar, David G. Ashbrook, Alistair Senior, Marin E. Nelson, Nicholas R. Pannunzio, Selma Masri, Evgeny Z. Kvon, Grant MacGregor, Cholsoon Jang, Vittorio Sebastiano, Minji Byun, Changrui Xiao, Alexander S. Kauffman, Robert W. Williams, David E. James, Ivan Marazzi, Dequina Nicholas, Marcus Seldin
×Abstract
Resistance to CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy presents a major barrier to improving outcomes in ER+ breast cancer. We identified FADD phosphorylation at Ser194 (phospho-FADD) as a mediator of CDK4/6i resistance in the models examined. Phospho-FADD acted as a pseudosubstrate inhibitor of the APC/C-Cdh1 complex, promoting G1/S transition and bypassing the canonical CDK4/6-Rb-E2F pathway. This CDK4/6-independent pathway was associated with PI3K hyperactivation. Clinical relevance of this bypass pathway was supported by increased phospho-FADD and pAKT in 73% of paired patient biopsies at posttreatment recurrence, while the remaining cases exhibited high baseline phospho-FADD and pAKT with intrinsic nonresponse. Inhibition of FADD phosphorylation with the CK1α degrader DEG-77, or PI3K inhibition, restored CDK4/6i sensitivity in resistant cells. In CDK4/6i-refractory xenografts, CK1α degradation combined with CDK4/6i resulted in profound tumor regressions and increased progression-free survival compared with either single agent, including complete tumor regressions in 92% of tumors. These findings support CK1α-mediated FADD phosphorylation as a targetable resistance mechanism in a subset of CDK4/6i-resistant ER+/HER2– breast cancer.
Authors
Sahezeel Awadia, Elizabeth K. Ziemke, Nicole M. Curnutt, Emily Kirk, Julianne Thomas, Anna Zimmerman, Maya J. Mileski, Sundaresh Ram, Reine Abou Zeidane, Craig Galban, Christina M. Woo, Corey W. Speers, Judith Sebolt-Leopold, Alnawaz Rehemtulla
×Abstract
Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.
Authors
Yingying Zhang, Chen Yu, Xiaoqin Zhang, Linda Xiaoyan Li, Alice Shasha Cheng, Xiaogang Li
×Abstract
When massive hepatic necrosis–associated (MHN-associated) acute liver failure (ALF) occurs following severe damage, liver progenitor cells (LPCs) exit quiescence and enter differentiation programs during which they acquire hepatocyte-like functions. How LPCs maintain quiescence under physiological conditions and orchestrate activation following MHN remains largely unknown. We elucidate an essential role of TGF-β in regulating LPC quiescence and activation. Spatial transcriptomics and single-cell sequencing revealed that LPCs receive multiple signals, particularly TGF-β, HGF, and EGF, from surrounding hepatic stellate cells and macrophages in patients and zebrafish with MHN-induced ALF. Physiologically, TGF-β inhibits LPC proliferation by blocking G1-to-S phase transition, an effect reversed by Smad7 overexpression in a murine injury model. We observed extensive LPC proliferation in patients with ALF despite strong TGF-β/phosphorylated SMAD signaling. Immunostaining revealed concurrent activation of HGF/MET, EGF/EGFR, and downstream STAT3/ERK pathways in LPCs. In vitro, HGF or EGF overcame TGF-β–mediated growth arrest and promoted LPC proliferation. Beyond acting as a mitogen, HGF additionally induced hepatocyte gene programs (e.g., Hnf4a, Hnf1a) in LPCs. Strikingly, TGF-β signaling was required for HGF-dependent hepatocyte gene induction, indicating a dual role in restraining LPC proliferation and promoting functional maturation. These findings position TGF-β as a context-dependent determinant of LPC activation and lineage specification during ALF.
Authors
Chenhao Tong, Tao Lin, Han Wang, Luyao Jiang, Xiaodong Yuan, Wenwu Luo, Minghan Zhou, Carolina De La Torre, Hui Liu, Chen Shao, Seddik Hammad, Hui Gao, Jiarong Xie, Lei Xu, Roman Liebe, Zuguang Gu, Matthias P. Ebert, Huiguo Ding, Steven Dooley, Hong-Lei Weng
×Abstract
During early pregnancy, maternal blood surrounds the embryo before the placenta is fully developed, requiring tight regulation of maternal blood flow into the placental vasculature. We identify placental microthrombi (PMTs) as essential structures guiding this process. PMTs contain platelets, coagulation factors, and complement proteins, and their formation depends on maternal platelet activation by thrombin through the protease-activated receptor 4 (PAR4). Deficiency of PAR4 abolished PMTs and caused excessive bleeding at the implantation site. C3 deficiency also led to increased bleeding events, indicating that complement activation contributes to thrombosis in the placental circulation. Conversely, dysregulated complement activation in CMP–sialic acid synthase–deficient (Cmas–/–) mice led to widespread thrombosis and failed placental development. Strikingly, platelet activation via PAR4 was necessary to localize complement activation to trophoblast surfaces, thereby coupling coagulation and complement in PMT formation. Depletion of maternal platelets mitigated complement-driven thromboinflammation in Cmas–/– pregnancies, restoring placental growth. These findings uncover a critical cooperation between platelets, coagulation, and complement in establishing maternal blood flow to the placenta. Successful pregnancy therefore requires not only activation but also tight regulation of these systems to balance necessary PMT formation with the prevention of pathological thrombosis.
Authors
Arno Smid, Lisa Schumann, Olga Oleshko, Ulrike Peters-Bernard, Kerstin Flächsig-Schulz, Melissa Whitehead, Emma Arndt, Korbinian Brand, Sonja Werwitzke, Andreas Klos, Bryan Paul Morgan, Wioleta M. Zelek, Andreas Tiede, Markus Abeln
×Abstract
Neddylation is highly activated in many human cancers and may serve as a therapeutic target for clinical treatment. However, the role of neddylation in tumor angiogenesis remains unclear. Here, we demonstrate that the neddylation E2 enzyme UBE2M was upregulated in tip cells and was essential for tumor vascular sprouting. We showed that UBE2M-mediated neddylation of STAT1 enhanced its phosphorylation and promoted the transcription of DLL4. This elevated DLL4 expression in tip cells activated Notch signaling in adjacent stalk cells, thereby maintaining the tip-stalk cell balance and ensuring organized vascular patterning. Consequently, endothelial cell–specific deletion of UBE2M reduced DLL4 expression, leading to excessive but nonproductive sprouting due to uncontrolled tip cell formation and lack of stalk cell support, which ultimately suppressed tumor growth. Importantly, targeting endothelial neddylation potently sensitized various tumors to anti-VEGF therapy. Together, our findings unveil UBE2M as a key regulator of angiogenic signaling and identify it as a promising antiangiogenic target in cancer.
Authors
Xinyi Jiang, Jie Zhang, Li Zhou, Zonglin Li, Ningcong Sun, Xian Xu, Jisong Zhang, Yizhou Huang, Xue Zhang, Enguo Chen, Hongqiang Cheng, Yuehai Ke
×Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.
Authors
Bingge Zhang, Ye He, Ting Su, Xiaomei Li, Xiufen Zhang, Ruijuan Liu, Xiao Han, Ruiming Zhang, Chao Yang, Xinlei Liu, Qinghua Hou, Zaijun Zhang, Yongmei Xie, Gongping Liu, Xifei Yang
×Abstract
Ex vivo engineering strategies for adoptive αβ T cell therapies increasingly use pharmacological modulation to improve survival, expansion, and antitumor activity. Short-term exposure to the B cell lymphoma-2 (BCL-2) inhibitor venetoclax during αβ T cell manufacturing enhances apoptotic priming and effector persistence, suggesting a route to strengthen other T cell lineages. γδ T cells share cytotoxic properties with αβ T cells but recognize targets independently of major histocompatibility complex and show low alloreactivity, supporting off-the-shelf use in acute myeloid leukemia (AML). Whether such conditioning benefits γδ T cells was unknown. Here, we show that ex vivo venetoclax pretreatment enhances the antileukemic efficacy of therapeutic γδ T cells and chimeric antigen receptor (CAR) γδ T cells. Venetoclax-pretreated γδ T cells displayed increased cytotoxicity and proliferation with reduced exhaustion, yielding superior control of AML blasts and xenografts. These functional gains coincided with elevated mitochondrial content and a fatty acid oxidation metabolic profile. In vivo, venetoclax-pretreated γδ T cells achieved durable disease suppression, and the same conditioning improved CAR γδ T cell efficacy. Together, these results show that short-term BCL-2 inhibition enhances γδ T cell cytotoxicity and persistence. Incorporating venetoclax pretreatment into γδ T cell manufacturing may improve therapeutic efficacy and inform next-generation γδ T cell therapies for AML.
Authors
Xingchi Chen, Lin Zhang, Bingbing Yan, Yinqiang Sui, Weiwei Ma, Hui Zhao, Yining Wang, Kepeng Yang, Jiewen Ma, Baolin Tang, Yonghui Zhang, Xiaoyu Zhu
×Abstract
Autosomal dominant polycystic kidney disease (ADPKD) accounts for 5%–10% of prevalent end-stage kidney failure (ESKD). ADPKD cysts result from a loss of sufficient functional expression of PKD1/Polycystin-1 (PC1) in approximately 80% of families. Kidney disease severity correlates with the extent to which PC1 dosage is reduced below a critical level, and evidence suggests therapeutic benefit from increasing PC1 expression in these conditions. Upstream open reading frame (uORF) translation can reduce translation of a protein’s coding sequence. Ribosome profiling data and bioinformatic predictions suggested the presence of conserved PKD1 uORFs, so we sought to explore their biological role. We generated luciferase reporters and two humanized PKD1 5’ UTR mouse models with or without single nucleotide edits removing uORF start codons (ΔuORF) to define active uORFs and test their impact on PC1 translation. PKD1 uORF start codons can robustly initiate translation, and ΔuORF conveys a 2–4 fold increase in PC1 protein expression and resultant prevention of kidney cysts in Dnajb11 as well as in Pkd1 missense models. PKD1 uORF1-blocking steric antisense oligonucleotides (ASOs) substantially increase PC1 expression in vitro. PKD1 uORFs play an important role in the low basal expression of WT PKD1, and their inhibition represents an opportunity to therapeutically increase PC1 translation in polycystic kidney and liver disease resulting from reduced dosage of PC1.
Authors
Zhigui Li, Zi Guo, Soyoung Cho, Rishi Bhardwaj, Ke Dong, Sorin Fedeles, Whitney Besse
×Abstract
Hepatic stellate cell (HSC) activation can lead to liver fibrosis, for which there are no effective treatments. Aberrant cytoskeletal reorganization is a central driver of HSC activation. Non-muscle myosin II (NM II) is known to regulate cytoskeleton remodeling via its actin cross-linking and contractile properties. However, the molecular players controlling actomyosin assembly and contractility in HSCs during liver fibrosis remain poorly defined. Here, we identified integrin β-like 1 (ITGBL1) as a gatekeeper of HSC quiescence by negatively regulating actomyosin contractility-driven mechanotransduction in HSCs. ITGBL1 expression was markedly elevated in activated HSCs found in patient and mouse fibrotic livers. Unexpectedly, HSC-specific Itgbl1 deficiency worsened liver fibrosis, whereas ITGBL1 overexpression in HSCs limited it, suggesting a protective role for ITGBL1 against a pathogenic HSC activation. Multiomics and functional analyses revealed that ITGBL1 impaired F-actin filament organization in HSCs by disrupting actomyosin assembly dependent on myosin heavy chain 9 (MYH9, also named NM II heavy chain A). In line, HSC-specific Myh9 deficiency or silencing of Myh9 in HSCs alleviated liver fibrosis. Taken together, our findings unveil that ITGBL1-MYH9 interaction acts as a critical mechanoregulatory brake that maintains cytoskeletal equilibrium and mechanical homeostasis in HSCs, providing a promising therapeutic strategy to combat liver fibrosis.
Authors
Yixin Li, Yan Wang, Chenhao Tong, Xinghuan Fu, Ningning Ma, Yawen Hao, Zian Feng, Shijia Ling, Zequn Yin, Haodong Li, Shujun Ge, Siting Yang, Peng Xiao, Siyue Dong, Adrien Guillot, Yajun Duan, Yong He
×Abstract
BACKGROUND Despite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODS To better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTS Our study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSION RD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATION ClinicalTrials.gov NCT00861705.FUNDING NIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.
Authors
Patrick D. Rädler, Brooke M. Felsheim, Aranzazu Fernandez-Martinez, Adam D. Pfefferle, Michele C. Hayward, Baljit Singh, William Sikov, Lisa A. Carey, Charles M. Perou
×Abstract
Tregs in visceral adipose tissue (VAT) play essential roles in systemic metabolic homeostasis under distinct physiological and pathological conditions. However, the metabolic cues that drive Treg subset specialization in the obese VAT niche remain elusive. Here, we demonstrated that palmitic acid (PA) instigated chronic VAT inflammation and systemic metabolic disturbance by compromising the immunosuppressive function of the ICOShi Treg subset. PA, but not oleic acid, activated CREB/ATF bZIP transcription factor (Crebzf) expression in VAT Tregs from high-fat, high-sucrose diet–induced (HFHS diet–induced) obese and ob/ob mice. Crebzf deficiency significantly attenuated diet-induced obesity and inflammation by upregulating the suppressive function of VAT ICOShi Tregs. Moreover, adoptive transfer of Crebzf-deficient ICOShi Tregs into Rag1–/– mice alleviated HFHS diet–induced inflammation and metabolic disorders more effectively than transfer of Crebzf-sufficient ICOShi Tregs. Mechanistically, CREBZF interacted with c-JUN to inhibit Foxp3 activity, thereby impairing the stability and inhibitory cytokine production of ICOShi Tregs. In humans, CREBZF levels in VAT Tregs were elevated and negatively correlated with FOXP3 activity. Collectively, these findings uncover a specific ICOShi Treg subset that responds to PA, thereby coupling obesogenic signals to VAT remodeling and systemic metabolic homeostasis.
Authors
Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li
×Abstract
BACKGROUND B cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma (MM), yet its whole-body in vivo distribution and role in disease assessment remain incompletely defined. We aimed to evaluate the safety, diagnostic performance, and clinical utility of a novel BCMA-targeted PET tracer, 68Ga-PFBC01, in patients with plasma cell disorders.METHODS We conducted a single-center, prospective, single-arm phase I trial (ClinicalTrials.gov NCT06717113). Fifty patients underwent 68Ga-PFBC01 PET/CT, including 40 with paired 18F-FDG PET/CT for head-to-head comparison. Primary outcomes included diagnostic performance (sensitivity, specificity, PPV, NPV, and interreader agreement). Secondary outcomes included correlations with clinical biomarkers, treatment response assessment, impact on clinical decision-making, and safety.RESULTS 68Ga-PFBC01 PET/CT demonstrated superior diagnostic performance compared with 18F-FDG PET/CT (sensitivity 96.9% versus 84.6%; specificity 71.4% versus 60.0%). Quantitative PET-derived tumor burden correlated with M protein (R = 0.325, P = 0.026), free light chains (R = 0.340–0.437, P ≤ 0.015), soluble BCMA (R = 0.433, P = 0.050), and bone marrow plasma cells (R = 0.682, P < 0.001). Imaging findings altered clinical management in multiple cases, enabling both therapy escalation and deescalation. Blood-pool uptake strongly correlated with soluble BCMA (R = 0.899, P < 0.001) and overall disease burden (R = 0.736, P < 0.001). No serious tracer-related adverse events were observed; 2 patients (4%) experienced mild events.CONCLUSION 68Ga-PFBC01 PET/CT provides biologically specific, whole-body assessment of MM, outperforming 18F-FDG and enabling integrated evaluation of tumor burden and systemic disease activity, with direct implications for clinical decision-making.TRIAL REGISTRATION ClinicalTrials.gov NCT06717113.FUNDING National Natural Science Foundation of China (82472018, 82402320), Beijing Nova Program (20240484725), National High Level Hospital Clinical Research Funding (Interdisciplinary Research Project of Peking University First Hospital, 2024IR07, Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2025CX38, 2024CX18). Research Achievement Transformation Project of Peking University First Hospital, 2025ZH02), Clinical Medicine Plus X - Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities (PKU2026PKULCXQ038).
Authors
Tingfei Gu, Zhao Chen, Bo Tang, Tianyao Wang, Qi Yang, Huihui Liu, Zeyin Liang, Qian Wang, Yang Zhang, Yuhua Sun, Mingyi Di, Tingting Yuan, Yongkang Qiu, Yimeng Du, Lele Song, Shengnan Wu, Wei Wang, Xiaojie Xu, Yujun Dong, Lei Kang
×Abstract
Loss-of-function mutation in the human gene dipeptidyl peptidase 9 (DPP9) causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia, and patients require bone marrow transplantation, but the mechanism of cell loss is unclear, since Dpp9-mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34+ hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However, DPP9 deletion led to few transcriptional changes suggesting posttranscriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to activation of the CARD8 inflammasome, resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.
Authors
Tianli Xiao, J. Richard Brewer, Maximillian Carlino, Ailin Han, Yamato J. Takabe, Chia-Yi Lee, Fengrui Zhang, Mi Chen, Holly Nicole Blackburn, Amin H. Nassar, Qiankun Wang, Kristen Brennand, Liang Shan, Esen Sefik, Diane S. Krause, Richard A. Flavell
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Abstract
STXBP1 variants are a frequent cause of early-onset developmental and epileptic encephalopathies and related neurodevelopmental disorders, but the clinical interpretation of these variants remains a major challenge. Most reported STXBP1 missense variants are classified as variants of uncertain significance (VUS), complicating diagnosis, counseling, and patient eligibility for precision therapies. Here, we developed EpiPred, a gene-specific machine learning classifier that predicts the pathogenicity of STXBP1 missense variants and tests these predictions using empirical evidence from well-established cellular assays. Trained on a curated set of pathogenic and benign variants, EpiPred outperformed global prediction tools in accuracy, sensitivity, and specificity. We validated the model’s predictions using variant effect assays that measure protein abundance, solubility, stability, and interaction with the SNARE complex partner syntaxin 1. These biochemical readouts aligned closely with model outputs and enabled reclassification of several possibly misdiagnosed variants, which warrant further validation and clinical reevaluation. We deployed EpiPred in an interactive web application that allows clinicians, researchers, and patients to explore predictions for all possible STXBP1 missense variants. By identifying likely pathogenic STXBP1 variants, including those that may respond to emerging therapies such as protein stabilizers. By coupling gene-calibrated machine learning with orthogonal variant-effect assays and public deployment, EpiPred provides a transferable framework for VUS resolution, trial enrichment, and precision diagnosis across clinically actionable Mendelian disease genes.
Authors
Jeffrey D. Calhoun, Chengbing Wang, Carina G. Biar, Jonathan R. Gunti, John S. Lee, Aaron M. Geller, Jung H. Hong, Santiago Schnell, Louis T. Dang, Yu Wang, Jack M. Parent, Lori L. Isom, Michael D. Uhler, Heather C. Mefford, M. Elizabeth Ross, Vanessa Aguiar-Pulido, Gemma L. Carvill
Abstract
Advanced prostate cancer has increasingly developed a lethal neuroendocrine form, small cell/neuroendocrine prostate cancer (NEPC), as a consequence of the widespread use of highly potent androgen receptor signaling inhibitors in castration-resistant disease. The molecular mechanisms remain unclear and no effective therapies currently exist. We report that tryptophan hydroxylase 1 (TPH1), the enzyme responsible for peripheral serotonin biosynthesis — a neurotransmitter enriched in neuroendocrine tumors and a classical neuroendocrine biomarker — was upregulated in both de novo and therapy-induced human NEPC. TPH1 upregulation was necessary and sufficient for neuroendocrine differentiation and the NEPC phenotype through its enzymatic activity. Silencing TPH1 suppressed neuroendocrine plasticity and various aggressive behaviors of NEPC cells, including proliferation, invasion, sphere formation, and NEPC tumor xenograft growth. Mechanistically, TPH1 activated mTOR via intracellular serotonin-dependent serotonylation of mTOR at glutamine 2453, which triggered the induction of FOXM1 and E2F1 to drive NEPC differentiation and growth. Importantly, pharmacological inhibition of TPH1 using the clinically available inhibitor LX1606 effectively restricted growth and neuroendocrine marker expression in multiple NEPC cell lines and patient-derived xenografts. Collectively, these findings characterize TPH1’s contribution to NEPC and suggest TPH1 as a potential therapeutic target.
Authors
Jing Wei, Jing Wang, Jingrui Chen, Michelle Zhang, Chia-Hui Chen, Tianjie Pu, Alivia O'Brien, Sephtis Hargrove, Eva Corey, Tzu-Ping Lin, Allen C. Gao, Boyang Jason Wu
Abstract
Pharmacologic immunosuppression is essential for preventing organ rejection and controlling autoimmunity, but profoundly impairs humoral immunity, increasing the risk of vaccine failure and infection. The mechanisms by which immunosuppressive therapies disrupt human B cell responses remain poorly defined. Here, we identified dysregulated lipid metabolism as a central determinant of impaired vaccine response in solid organ transplant recipients (SOTRs). Using high-dimensional immune profiling, single-cell transcriptomics, and functional metabolic assays, we found that effective B cell responses required a homeostatic balance between lipid synthesis and fatty acid oxidation. The widely used immunosuppressive agent, mycophenolic acid (MPA) was strongly associated with vaccine non-response and induced excessive lipid synthesis, lipid accumulation, and mitochondrial stress in B cells. In contrast, CD11c+ B cells retained the capacity to differentiate into plasmablasts in the presence of MPA through elevated expression of CPT1A, a mitochondrial fatty acid transporter, and enhanced fatty acid oxidation. These cells were found to be a key feature of early effective vaccine responses in healthy individuals and SOTRs. Notably, pharmacologic inhibition of cholesterol synthesis partially restored plasmablast differentiation in the presence of MPA. These findings identify B cell lipid metabolism as a critical and targetable regulator of human humoral immunity during immunosuppression.
Authors
Elizabeth A. Thompson, Alexis Figueroa, Katerina Roznik, Nicole E. Skinner, Santosh Dhakal, Shuai Li, Luca Biavati, Laura A. Sena, Laila Stoddart, Karli Redinger, Samuel B. Warner, Sabra L. Klein, Nadine Rouphael, Joel N. Blankson, Yolanda Eby, Robert D. Leone, Peter S. Heeger, Mark A. Robien, Christian P. Larsen, Erika L. Pearce, Edward J. Pearce, Hongkai Ji, Andrew H. Karaba, Dorry L. Segev, Aaron A.R. Tobian, William A. Werbel, Andrea L. Cox, Justin R. Bailey
Abstract
GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Here, we silenced Glp1r neurons in the nucleus of the solitary tract or area postrema (NTSGlp1r or APGlp1r neurons, respectively) or restored their GLP1R signaling on an otherwise GLP1R-deficient background to determine physiological and pharmacological roles for each neuron population. Although NTSGlp1r neurons contributed to the normal restraint of food intake and body weight, they failed to mediate GLP1RA-dependent weight loss. In contrast, while we detected no role for APGlp1r neurons in physiological feeding, they mediated both the weight-lowering and aversive effects of GLP1RAs. Therefore, while non-aversive NTSGlp1r neurons control physiologic satiation they do not contribute to weight loss during GLP1RA treatment. Rather, APGlp1r neurons mediate both the weight-lowering and aversive effects of GLP1RAs, preventing the separation of their nauseating and weight-loss effects at a circuit level.
Authors
Warren T. Yacawych, Yi Wang, Guoxiang Zhou, Shad Hassan, Cagri Bodur, Elisabeth Walters, John G. Santinga, Frederike Sass, Martin deVaux, Stace Kernodle, Iris Wu, Jenny M. Brown, Dylan M. Belmont-Rausch, Alan C. Rupp, Abigail J. Tomlinson, Zitian Lin, Emma VanTongeren, Anna Secher, Kirsten Raun, Tune H. Pers, Randy J. Seeley, Martin G. Myers Jr., Weiwei Qiu
Abstract
Obesity-associated inflammation impairs pancreatic β-cell function, yet the mechanisms by which immune cells acutely regulate insulin secretion remain poorly defined. Here, we identify myeloid Gq signaling as an immunometabolic node linking macrophage lipid sensing to impaired insulin secretion. Using chemogenetic DREADD-mediated activation of myeloid Gq, we show that acute macrophage Gq activation impairs glucose-stimulated insulin secretion (GSIS) in vivo, whereas myeloid Gαq ablation enhances GSIS. Mechanistically, Gq activation rapidly induced AMPK phosphorylation and sphingolipid remodeling independently of canonical inflammatory cytokines. Macrophage-derived sphingolipids impaired β-cell insulin signaling and GSIS through CD36-PKCζ, while inhibition of CD36, AMPK, or sphingolipid metabolism restored β-cell function. We further identified GPR18, a Gq-coupled endocannabinoid-responsive GPCR, as an upstream regulator. GPR18 activation with N-arachidonoyl glycine (NAGly) recapitulated this phenotype, whereas myeloid Gαq deletion or Gpr18/AMPK silencing abolished it. GPR18 signaling predominantly engaged Gq rather than Gi pathways. In human tissues, GPR18 was enriched in islet macrophages, and NAGly suppressed GSIS in primary human islets. Thus, a conserved macrophage GPR18-Gαq-AMPK-sphingolipid axis dynamically regulates β-cell function and represents a potential therapeutic target in obesity and type 2 diabetes.
Authors
Simran Singh, Ashish Kumar, Sudipta Paul, Mriganka Sarkar, Santhosh Duraisamy, Ganesh Timalsina, Raashidha Farhath, Harender Yadav, Seema Kuldeep, Soumita Bhaumik, Kunj Kumar Prajapati, Saahiba Thaleshwari, Anuj Gargya, Tamojit Santra, Sonal Amit, Rashmi Parihar, Santosh K. Misra, Hamim Zafar, Luiz F. Barella, Michael A. Kalwat, Dharmaraja Allimuthu, Sai Prasad Pydi
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Series edited by Alexander Stegh
The cGAS-STING pathway: DNA sensing in health and disease
Series edited by Alexander Stegh
The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is a key component of innate immunity, linking DNA detection to inflammatory and antiviral responses. Originally identified as a sensor for microbial DNA, cGAS is now understood to also respond to endogenous cytosolic DNA, and the pathway has been implicated in a wide range of physiological and pathological processes, including cancer, autoimmunity, neuroinflammation, and aging. This review series, organized by Dr. Alex Stegh, consolidates current knowledge and highlights emerging developments that may lead to therapeutic targeting of the cGAS-STING pathway across a range of disorders.
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