Issue published November 2, 2026 Previous issue
- Volume 136, Issue 21
On the cover:
KROX20 marks sebaceous gland stem cells
Zhang et al. report that transcription factor KROX20 marks sebaceous gland (SG) stem cells and regulates their differentiation to maintain skin oil balance. Ablation of KROX20-positive cells causes SG loss and rapidly and robustly induces dry and flaky skin. The cover image shows whole-mount SGs in the skin visualized by the lipophilic fluorescent dye Nile Red (magenta), with nuclei counterstained with DAPI (gray) to show the hair follicles. Image credit: Yumeng Zhang.
Zhang et al. report that transcription factor KROX20 marks sebaceous gland (SG) stem cells and regulates their differentiation to maintain skin oil balance. Ablation of KROX20-positive cells causes SG loss and rapidly and robustly induces dry and flaky skin. The cover image shows whole-mount SGs in the skin visualized by the lipophilic fluorescent dye Nile Red (magenta), with nuclei counterstained with DAPI (gray) to show the hair follicles. Image credit: Yumeng Zhang.
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Commentaries
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Abstract
Spinal muscular atrophy (SMA) is characterized by motor neuron degeneration due to deficiency in the survival of motor neuron (SMN) protein. Disease-modifying therapies have transformed outcomes in SMA, while also revealing an increasingly complex spectrum of residual disease biology. In this issue of the JCI, Tapken, Rahmel-Stein, and colleagues demonstrated cell-specific SMN expression and persistent alterations in peripheral immune cell populations in nusinersen- or risdiplam-treated adults with SMA. Their findings extend the question of selective vulnerability beyond motor neurons and raise an increasingly important therapeutic question: What constitutes adequate SMN restoration? This Commentary considers how cell type, developmental timing, SMN requirement, and downstream response may shape treatment-modified SMA, with implications for systemic and CNS-directed therapies.
Authors
Crystal Jing Jing Yeo
×Abstract
Growing evidence shows that the risk of cognitive impairment is increased across a range of metabolic and cardiovascular diseases, but underlying mechanisms remain poorly understood. One possibility involves activation of microglia, a glial cell type of the central nervous system with morphological and transcriptional features comparable to resident macrophages in other tissues that plays specialized roles in supporting neuronal and brain function. Combining clinical investigation in pulmonary arterial hypertension (PAH) cohorts with mouse model and microglial cell culture studies, a study by Okawa, Shi, and colleagues in this issue of the JCI adds compelling, albeit indirect, evidence linking impaired lysosomal lipid handling in both endothelial cells and microglia to a specific neurological disorder associated with PAH. The findings open opportunities for understanding how cardiopulmonary disease predisposes to neurodegeneration.
Authors
Michael W. Schwartz, Karin E. Bornfeldt
×Abstract
Combined CTLA-4 and PD-1 blockade is effective in treating melanoma and additional cancers but frequently causes immune-related adverse events (irAEs). irAEs cause treatment disruption and discontinuation and remain difficult to manage clinically. In this issue, Dhodapkar and colleagues assessed data from a small randomized clinical trial testing rituximab-mediated B cell depletion in combined CTLA-4/PD-1 blockade–treated patients with advanced melanoma. Despite premature discontinuation of the trial due to a high rate of rituximab hypersensitivity, they report that preemptive B cell depletion was associated with fewer severe toxicities without evident loss of antitumor activity. These findings raise broader questions about the organization of checkpoint-induced autoimmunity, the emerging concept of immune reset, and the compartment-specific roles of B cells in antitumor immunity.
Authors
Chuan-Yuan Li
×Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) arise from hormone-producing cells in the gut and pancreas. Despite increasing incidence of these tumors, therapeutic options remain limited. Well-differentiated GEP-NETs are classified by anatomic site, morphology, and proliferation indices, but this approach offers limited prognostic resolution among phenotypically similar tumors and constrains personalization of treatment decisions. In this issue of the JCI, Karam, Hoffman, and colleagues profiled 38 pancreatic and small-intestinal NETs using joint single-nucleus RNA and ATAC sequencing and projected the resulting malignant cell–associated programs onto matched spatial transcriptomes. Two conserved malignant states emerged: neuronal-like and secretory neuroendocrine. These states span a continuum in both organ sites, are enriched for largely different transcription factor motifs, and occupy distinct microenvironmental niches. Secretory program scores trended higher in metastatic disease and may carry prognostic value. Taken together, these data describe NET heterogeneity as a cell state axis linked to tissue architecture.
Authors
Parambir S. Dulai
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Research Articles
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Abstract
Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase enriched in the mammalian brain whose loss of function causes a severe developmental and epileptic encephalopathy named CDKL5 Deficiency Disorder. We previously showed that CDKL5 phosphorylates the microtubule-associated protein MAP1S, but how this regulates microtubule-dependent functions is not well understood. To address this question, we generated MAP1S phosphomutant mice in which the CDKL5 phosphorylation sites S786 and S812 were mutated to alanine (MAP1S S786/812A; MAP1S SA). Using a microtubule cosedimentation assay, we found that dynein binding to microtubules was reduced in MAP1S SA and CDKL5 knockout (KO) brain lysates, and time-lapse imaging showed impaired dynein motility in dendrites from both genotypes. MAP1S SA mice also exhibited reduced AMPA receptor transport, dendritic spine density, and excitatory synapses, accompanied by anxiety-like behavior and motor, social, and memory deficits relevant to CDD. Mechanistically, MAP1S SA and CDKL5 KO neurons showed increased microtubule stability and reduced tubulin tyrosination, consistent with excessive MAP1S-mediated stabilization. Restoring tubulin tyrosination by expressing tubulin-tyrosine ligase rescued dynein transport defects. Together, these findings identify MAP1S phosphorylation as a critical regulator of microtubule dynamics and dynein-dependent transport.
Authors
André T. Lopes, Ondine Janiv, Suzanne Claxton, Sila K. Ultanir
×Abstract
A significant challenge for improving the efficacy of immune checkpoint blockade (ICB) therapy is the concurrent activation of Tregs, which can dampen antitumor responses. Thus, elucidating the mechanisms that maintain Treg-suppressive function within the tumor microenvironment is critical. Here, we identified an accumulation of N-acetyltransferase 10–modified (NAT10-modified) RNA, particularly in NAT10+FOXP3+ Tregs, in human non–small cell lung cancer. Genetic ablation of Nat10 in tumor-infiltrating (TI) Tregs, or pharmacological inhibition of NAT10 expression, significantly reduced the PD-1+ Treg/CD8+ T cell ratio. These effects were accompanied by an increase in IFN-γ+ Tregs, a reduction in the immunosuppressive activity of Tregs, and inhibition of tumor progression. Mechanistically, NAT10 promotes TI Treg infiltration and activation independently of its RNA-modifying function by directly interacting with FOXP3 and chromatin, modulating local 3D chromatin contacts. Combined administration of anti–PD-1 antibodies and a NAT10 inhibitor further impaired TI Treg–mediated immunosuppression, leading to enhanced tumor control. Our findings demonstrate that NAT10 is a key regulator of TI Treg fragility and function and that its inhibition may enhance the therapeutic efficacy of ICB.
Authors
Xuewei Qi, Dan Cui, Xiao Li, Wenfan Fu, Handong Ma, Wenting Guo, Jiabao Wang, Jiaxi Song, Jiaxin Ma, Jing Yang, Haoyu Yu, Yuting Hong, Qian Wang, Susu Luo, Jia Wang, Baixing Wu, Shanshan Li, Hao Cheng, Min Cheng, Bin Li, Kaiming Zhang, Jia Li, Fengyin Li
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Membranous nephropathy (MN) is an autoimmune kidney disease and a major cause of nephrotic syndrome in adults. Although autoantibodies against phospholipase A2 receptor 1 (PLA2R) and complement activation are central to disease pathogenesis, the mechanisms by which anti-PLA2R antibodies activate complement at the podocyte surface remain incompletely defined. Here, we cloned 14 patient-derived anti-PLA2R mAbs and found that they predominantly recognized the N-terminal cysteine-rich (CysR) and C-type lectin domain 1 (CTLD1) regions of PLA2R. Individual anti-PLA2R mAbs induced little or no complement-dependent cytotoxicity (CDC) of PLA2R-expressing podocytes in vitro. In contrast, paired mAbs targeting distinct epitopes, particularly CysR and CTLD1, markedly enhanced CDC. This effect was strongest for IgG1 and IgG3 antibodies, whereas IgG4 alone did not activate complement but modulated CDC in combination with IgG1. Purified IgG from patients with PLA2R-associated MN similarly induced CDC, which was augmented by addition of anti–PLA2R IgG1 and reduced by anti–PLA2R IgG4 or Fab fragments targeting CysR or CTLD1. In human PLA2R–expressing mice, paired anti-PLA2R antibodies increased glomerular complement deposition and induced albuminuria. These findings identify epitope pairing as a key determinant of complement activation in PLA2R-associated MN and support epitope-specific targeting strategies as a promising avenue for therapeutic intervention.
Authors
Tsai-Yi Wu, Kun-Hua Tu, Larissa Seifert, Kung-Wei Lin, Han-Po Shih, Yu-Fang Lo, Jhan-Jie Peng, Gunther Zahner, Oliver Kretz, You-Ning Lin, Chen-Xuan Kang, Jing-Ya Ding, Yi-Ran Tu, Li-Yi Ma, Ya-Ting Chuang, Chia-Chi Lo, Yu-Huan Tsai, Chih-Wei Yang, Nicola M. Tomas, Cheng-Lung Ku
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Glucagon-like peptide 1 (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, however, 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. Here, we silenced Glp1r neurons in the nucleus of the solitary tract (NTS) or area postrema (AP) (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 nonaversive NTSGlp1r neurons controlled physiologic satiation they did not contribute to weight loss during GLP1RA treatment. Rather, APGlp1r neurons mediated 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 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
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Connections between vascular and neurocognitive diseases are emerging but remain poorly defined. Cognitive impairment is increasingly recognized in pulmonary hypertension (PH), a disease traditionally viewed as limited to the heart and lungs. Given that inflammation is shared by PH and neurodegenerative diseases, we investigated its role in driving brain and cognitive deficits in PH. Using structural and functional MRI data from UK Biobank (N = 248 PH) and a prospective validation cohort, we identified reduced cerebellar white matter volume, thinner frontal gyri, and weakened cerebellar-frontal connectivity in patients with PH but not in other heart or lung diseases. These changes were accompanied by worsened executive function and processing speed. Olink proteomics and targeted genomics linked inflammatory plasma proteins and a PH-associated nuclear receptor coactivator 7 (NCOA7) single nucleotide polymorphism, rs11154337, to these deficits. PH cerebellum showed increased microglial activation and white matter derangement. In PH mice, Ncoa7 deficiency worsened cerebellar inflammation and atrophy. Microglial functional assays, cerebellar single-nucleus RNA sequencing, and spatial transcriptomic analyses further implicated Ncoa7-dependent lysosomal, inflammatory, and cell-specific mechanisms of cerebellar pathobiology. These findings identify NCOA7-linked inflammatory dysfunction in the cerebellar-frontal axis in PH, redefining this disease with neurologic consequences and thus offering neural targets for diagnostic, prognostic, and therapeutic development.
Authors
Satoshi Okawa, Yinan Shi, Somanshu Banerjee, Yi Yin Tai, Jamal Nabhanizadeh, Stefan Guenther, Anisha N. Shah, Siyi Jiang, Timothy Kim, Yassmin Al Aaraj, Caroline Pidro, Metin Aytekin, Omolara Fatukasi, Nishita Kalepalli, Joseph Mettenburg, Timothy D. Girard, James T. Becker, Kathiravan Kaliyappan, Shanshan Song, Sandra Breuils-Bonnet, Steeve Provencher, Sébastien Bonnet, Theodore Huppert, Lloyd D. Harvey, Seyed Mehdi Nouraie, Rajkumar Savai, Dandan Sun, Soban Umar, Soni S. Pullamsetti, Stephen Y. Chan
×Abstract
BACKGROUND TGF-β drives fibroblast activation in cancer and is a resistance biomarker to PD-1/PD-L1 blockade.METHODS Focusing on the tumor stroma, we characterized the impact of neoadjuvant treatment with bintrafusp alfa (BA), a dual PD-L1 and TGF-β inhibitor, in a window-of-opportunity study with 6 patients with head and neck squamous cell carcinoma (HNSCC). Tumor biopsies before treatment and 3 weeks after therapy were analyzed using scRNA-seq, imaging, and spatial transcriptomics.RESULTS After treatment, we observed significantly decreased levels of activated LRRC15+ cancer-associated fibroblasts (CAFs), remodeled stromal architecture with reduced collagen I and XII content, and increased CD8+ T cell infiltration in immune-excluded tumors. These changes were independently confirmed in an additional neoadjuvant BA-treated cohort of 6 patients with HNSCC. The drastic CAF and stromal compartment reduction observed indicated a fibroblast depletion rather than a fibroblast polarization shift.CONCLUSION While our final clinical cohort does not allow assessment of the treatment effect, this study demonstrated that targeting TGF-β in patients can disrupt the tumor stroma within a short time frame. Further trials and novel biomarkers are now needed to select patients who could benefit.TRIAL REGISTRATION ClinicalTrials.gov NCT04428047.FUNDING Merck KGaA, ARC Emerging Leaders in Oncology, ANR-10-IDEX-0001-02 PSL, Centre d’Investigation Clinique IGR-Curie 1428, Site de Recherche Intégrée sur le Cancer (INCa-DGOS-Inserm-ITMO cancer_18000), French Government “Investissements d’Avenir” program, France 2030 program, Fondation pour la Recherche Médicale, Marie Skłodowska-Curie grant agreement 847718, Cooperative Research and Development Agreement with EMD Serono, and NIH (ZIA BC 010666).
Authors
Caroline Hoffmann, Jan-Timon Werle, Philémon Sirven, Mamy Andrianteranagna, Jocelyn Gal, Wiem Lassoued, Jerzy Klijanienko, Jeremy Mesple, Benjamin Demaille, Abdenour Abbas, Valentine Gauthier, Kyra J.E. Borgman, Isabelle Puisieux, Serena Janho dit Hreich, Olivier Choussy, Gregoire Marret, Sonia Lameiras, Nathalie Badois, Antoine Dubray-Vautrin, Gilles Dolivet, Lionnel Geoffrois, Renaud Leclère, Wail Zeitouni, Noemie Robil, Jane Merlevede, Altynbek Zhubanchaliyev, Maud Kamal, Ivan Bieche, Laure Monard, Clotilde Simon, Delphine Louis, Clint T. Allen, Arun Rajan, James L. Gulley, Maude Guillot-Delost, Christophe Le Tourneau, Hélène Salmon
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Secondary malignancies are the most feared adverse effects of cancer therapies. In this study, we explored the cutaneous oncogenic effects of the JAK inhibitor ruxolitinib. First, we demonstrated an epidemiological association between ruxolitinib exposure and development of aggressive cutaneous squamous cell carcinoma (cSCC) by analyzing international pharmacovigilance data and conducting a large cohort study. We next demonstrated the causal link between ruxolitinib treatment and cSCC development using in vitro and in vivo models. Mechanistically, we revealed that ruxolitinib induces transformation of premalignant keratinocytes by activating the MAPK pathway. This effect is mostly driven by JAK2 inhibition, suggesting a pharmacological class effect. To unravel the mechanistic underpinnings of ruxolitinib-induced MAPK activation, we then applied a phosphoproteomic approach. Alternative MAPK signaling downstream of the kinase COT was pinpointed as the main activator of the pathway in this context. The central role of COT was functionally validated using chemical inhibition, genetic impairment, and inactivated COT mutant expression. Indeed, impairment of COT rescued the pro-oncogenic effect of ruxolitinib. Finally, we determined using a combination of epidemiological, in vitro, and in vivo studies that ruxolitinib-mediated oncogenic effects also result in an increased risk of melanoma, suggesting that the uncovered cellular signaling mechanism might be extrapolated to other cancers with a high dependency on the MAPK pathway.
Authors
Hélène Pasquer, Antoine Forget, Maxime Battistella, Raphael Marie, Léa Provent, Barouyr Baroudjian, Emmanuelle Latour, Cécile Culeux, Blandine Roux, Khansa Saadallah, Amandine Gouverneur, Maxime Demourgues, Fanélie Jouenne, Jérôme Lambert, Bérangère Lombard, Damarys Loew, Sophie Tartare-Deckert, Lionel Adès, Emmanuel Raffoux, Bruno Cassinat, Juliette Soret-Dulphy, Pernelle Noize, Samia Mourah, Camille Lobry, Jean-Jacques Kiladjian, Alexandre Puissant, Céleste Lebbé, Lina Benajiba
×Abstract
Renal cell carcinoma (RCC) harbors an immunosuppressive tumor microenvironment that facilitates immune evasion and resistance to immune checkpoint blockade (ICB). However, the factors driving immune escape in RCC remain incompletely understood. In this study, transactivation response RNA-binding protein 2 (TARBP2) was identified as a critical regulator of the immune checkpoint molecule B7-H3. Elevated TARBP2 expression was associated with poor prognosis and ICB resistance in patients with RCC. Functionally, TARBP2 in RCC cells suppressed the intratumoral accumulation and cytotoxicity of T cells, particularly NK cells, thereby promoting immune escape. Mechanistically, nuclear TARBP2 interacted with p53-binding protein 1 (53BP1), inhibiting 53BP1 phase separation and subsequent p53 activation, thereby augmenting B7-H3 transcription. Furthermore, TARBP2 inhibition significantly enhanced ICB efficacy when combined with adoptive NK cell therapy. Collectively, these findings establish TARBP2 as a key mediator of immune evasion in RCC and a promising therapeutic target for overcoming ICB resistance.
Authors
Minyu Chen, Mingjie Lin, Jiangquan Zhu, Kezhi Liu, Guannan Shu, Zhuting Tong, Mi Zhou, Liangmin Fu, Taowei Yang, Yihui Pan, Xinwei Zhou, Jinchen Luo, Wuyuan Liao, Qihao Li, Lican Liao, Hansen Lin, Kangbo Huang, Lizhen Zhang, Wei Chen, Junhang Luo, Jiaxing Zhang
×Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, most of which are large exon deletions that result in loss of dystrophin protein. Adenine base editing (ABE) enables permanent gene correction by modifying splice sites to cause exon skipping and restoration of the DMD open reading frame. We previously demonstrated that adeno-associated virus 9–mediated (AAV9-mediated) delivery of adenine base editors allows efficient gene editing in mouse models of DMD. However, conventional AAV-based gene delivery approaches are complicated by their limited packaging capacity and high-dose-related toxicity. Here, we describe a single AAV vector encoding a compact adenine base editor, SlugABE8e, and a single-guide RNA, which enable efficient editing in a humanized DMD mouse model at a lower dose using the muscle-tropic MyoAAV4 capsid. Systemic MyoAAV4A delivery in juvenile DMD mice efficiently restored dystrophin expression in the heart and skeletal muscles. This molecular rescue was accompanied by reduced serum creatine kinase activity and diminished muscle pathology. A liver-detargeted MyoAAV4E-off capsid eliminated viral entry and editing in the liver. We also explored a high-fidelity base editor, SlugHF-ABE8e(V106W), which showed similar on-target and off-target editing to SlugABE8e. Together, these findings establish an all-in-one AAV strategy that efficiently mitigates DMD disease progression.
Authors
Yu-Chung Pien, Hui Li, Gabrielle Bulliard, Huachun Liu, Mateusz Z. Durbacz, Zhisheng Xu, Andreas C. Chai, Francesco Chemello, Efrain Sanchez-Ortiz, Nerea Zabaleta, Luk H. Vandenberghe, Ning Liu, Eric N. Olson
×Abstract
Mutations in the survival of motor neuron 1 (SMN1) can reduce functional SMN protein levels, which causes spinal muscular atrophy (SMA), a disease affecting the nervous system and peripheral tissues, including the immune system. Yet, SMN expression across immune cell subsets and the effect of SMN-modulating therapies on the immune system remain underexplored. We found that in neonatal mouse spleens, SMN expression was highest in B cells, and was massively reduced in SMA mice. In human PBMCs from adults, DCs and monocytes expressed the highest SMN levels, whereas patients with SMA showed reduced DC frequencies and increased B cell frequencies. Patients receiving systemic versus CNS-restricted therapy showed similar differences in immune cell composition and SMN expression levels. Similarly, an exploratory cohort including untreated patients did not show a substantial treatment-specific effect relative to controls. To assess the effect of differentiation on SMN, we analyzed PMA-treated THP-1 cells and found enhanced aberrant SMN splicing and increased SMN+ Cajal bodies. SMN levels varied across immune cell types, and reduced SMN levels were associated with altered immune cell composition. Immune alterations and decreased SMN levels were observed in both treated and untreated patients with SMA and may have contributed to dysfunctions of the immune system.
Authors
Ines Tapken, Katharina Rahmel-Stein, Christine Ehlers, Federica Cieri, Nora T. Detering, Tobias Schüning, Bogdan Bjelica, Charlotte Mindermann, Svenja Neuhoff, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Sabine Illsinger, Elia Di Schiavi, Theresa Graalmann, Susanne Petri, Ulrich Kalinke, Peter Claus
×Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic and spatial transcriptomic profiling across 38 well-differentiated pancreatic (PanNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed 2 conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program and a secretory neuroendocrine program. Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX:MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in PanNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that neuronal-like–high regions localized to densely cellular tumor areas with relative depletion of stromal infiltration, whereas secretory neuroendocrine–high regions occupied fibrovascular and stromal niches enriched for endothelial, fibroblast, and myeloid populations and associated with TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enriched for profibrotic and proangiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.
Authors
Julie Karam, Samantha E. Hoffman, Amanda Garza, Dan Gui, Hannah I. Hoffman, Breanna M. Titchen, Yutaro Tanaka, Erica Pimenta, Theodora Pappa, Laura Valderrabano, Kevin Bi, Riaz Gillani, Lauren Brais, Erin Shannon, Jason L. Hornick, Jihye Park, Jennifer Chan, Eliezer M. Van Allen
×Abstract
BACKGROUND Chronic kidney disease (CKD) and hypertension share common pathophysiological pathways contributing to vascular damage, endothelial dysfunction, and physical decline, particularly in older adults with prefrailty. To evaluate the relationship among renal injury, physical performance, and frailty progression in hypertensive older adults with CKD and assess whether dapagliflozin associates with reduced frailty progression, we designed the study DAPA-FORTRESS (DAPAgliflozin and Frailty prOgression in hypeRTension and chRonic kidnEy diSeaSe).METHODS We enrolled 135 prefrail hypertensive patients with CKD aged >65 years and followed them for 1 year. After coarsened exact matching, our balanced cohort had 105 patients (52 dapagliflozin). Associations between albuminuria, estimated glomerular filtration rate (eGFR), and physical performance were analyzed using correlation and regression models. Effect of dapagliflozin on frailty progression was evaluated using multivariable logistic regression.RESULTS A significant inverse association between gait speed and albuminuria (r2 = 0.48, P < 0.0001) and significant positive linear association between gait speed and eGFR (r2 = 0.18; P < 0.0001) were observed. Patients with eGFR <60 mL/min/1.73 m2 exhibited significantly worse physical performance than those with higher eGFR (P = 0.0003). In adjusted analyses, receiving dapagliflozin was independently associated with lower odds of progressing to frailty at 1 year (OR = 0.130; CI 0.045–0.381; P < 0.001).CONCLUSION In older hypertensive patients with CKD, greater renal injury is associated with worse physical performance, while dapagliflozin use reduces the risk of frailty progression. These findings indicate a potential protective role of sodium–glucose cotransporter 2 inhibition in mitigating functional decline in this high-risk population.FUNDING NIH: National Heart, Lung, and Blood Institute (R01-HL146691), National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK123259); American Heart Association (AHA- 24IPA1268813, AHA-22-915561, AHA-24-1195524).
Authors
Pasquale Mone, Davide Viggiano, Antonella Pansini, Maria Virginia Soldovieri, Giada Sabatelli, Valeria Visco, Gaetano Macina, Eugenio Boccalone, Michele Ciccarelli, Giuseppe Martinelli, Marco Di Mauro, Carmine Vecchione, Maria Morgante, Fahimeh Varzideh, Germano Guerra, Gaetano Santulli
×Abstract
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor critical for host defense against microbial infections. To prevent aberrant activation, nuclear cGAS is restrained by nucleosome tethering or by barrier-to-autointegration factor–mediated restriction of its access to DNA. However, its physiological roles beyond enzymatic suppression in the nucleus remain poorly understood. Here, we present a genome-wide map of cGAS chromatin localization in human cells and unexpectedly find its binding beyond nucleosome tethering, where cGAS is recruited to chromatin by AP-1 transcription factors via a potentially previously uncharacterized transactivation domain. Integrated CUT&RUN, RNA-seq, and metabolomics analyses reveal that cGAS transcriptionally regulates cholesterol homeostasis. Mechanistically, cGAS promotes LGALS3 transcription, which inhibits ACAA2 activity to suppress fatty acid oxidation and acetyl-CoA production, thereby lowering intracellular cholesterol levels. Reduced cholesterol lowers plasma membrane phosphatidylinositol [3,4,5] triphosphate [PI(3,4,5)P3] levels and decreases mTOR complex 2 (mTORC2) activation. In contrast, cGAS depletion results in cholesterol accumulation and elevated PI(3,4,5)P3, driving mTORC2/Akt signaling, promoting xenografted tumor growth, and conferring resistance to DNA-damaging agents. In vivo, the elevated hepatic cholesterol levels observed in cGas–/– mice were largely reversed by inhibition of Akt but not STING, whereas cGAS deficiency had minimal effects on lung physiology. Collectively, our findings uncover an unexpected role for nuclear cGAS in orchestrating a transcriptional program that links lipid metabolism to cell proliferation, stress response, and cholesterol homeostasis in liver.
Authors
Yu Deng, Matthew J. Niederhuber, Zhichuan Zhu, Austin J. Hepperla, Le Yu, Quentin Hahn, Joshua Hartsell, Tooba Rashid, Piotr A. Mieczkowski, Hemant Kelkar, Jeremy M. Simon, Yanqiong Zhang, Alessandra Livraghi-Butrico, Meredith J. Zeller, Joseph G.C. Kennedy, Jazmin F. DePriest, Jiong Li, Yan Zhang, Xing Qiu, H. Ümit Kaniskan, Jian Jin, Corbin D. Jones, Laura E. Herring, Douglas H. Phanstiel, Xiaojing Liu, Jesse R. Raab, Brian D. Strahl, Pengda Liu
×Abstract
BACKGROUND Combined checkpoint blockade (CCB) of programmed-death–1 (PD-1) and cytotoxic-T-lymphocyte–associated protein-4 (CTLA-4) is highly active in melanoma but limited by significant morbidity from immune-related adverse events (irAEs). Effective strategies to prevent CCB-mediated irAEs are lacking.METHODS Patients with advanced melanoma were randomly assigned to receive standard of care ipilimumab and nivolumab alone (Arm A: ipi/nivo, n = 7) or with one cycle of rituximab (Arm B; ipi/nivo+rituximab, n = 7).RESULTS Patients receiving ipi/nivo+rituximab experienced lower rates of greater than grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE–free survival compared with those in ipi/nivo arm (2-year G3-irAE-free survival 86% versus 29%, P = 0.01), without adverse impact on tumor regression or survival. G3 hypersensitivity reactions to rituximab (43% in Arm B) prompted trial closure. Rituximab depleted pretherapy activated naive B cells linked to autoimmunity and enhanced CCB-mediated induction of myeloid inflammation and CXCL13+ICOS+ CD4 T cells.CONCLUSION B cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk.TRIAL REGISTRATION ClinicalTrials.gov NCT03719131.FUNDING NIH CA238471, AR077926, CA289978, and CA290302.
Authors
Kavita M. Dhodapkar, Antonio Matera, Alyssa M. Duffy, Azmain Taz, Renee Julia Manalo, Melinda Yushak, Ragini Kudchadkar, David H. Lawson, Madhav V. Dhodapkar
×Abstract
Oil-producing sebaceous glands (SGs), attached to the upper/middle portion of hair follicles, are indispensable for maintaining skin hydration, and their dysfunction leads to dry skin. However, the molecular mechanisms underlying regulation of SG stem cells remain largely unknown. We identified transcription factor KROX20 as a marker of SG stem cells that sustains their stemness throughout SG morphogenesis and homeostasis. We developed an inducible mouse model in which ablation of KROX20-positive cells causes SG loss and rapidly and robustly induces dry, flaky, alopecia symptoms following induction. This model, termed xeroflacia (xero = xerosis, fla = flaky, cia = alopecia), provides a tool for studying the biology of dry skin. Furthermore, we found that KROX20 directly regulates Notch1 transcription to orchestrate the balance between SG stem cell self-renewal and differentiation. Small molecule drug modulation of Notch1 signaling to activate or inhibit the pathway enabled us to regulate SG differentiation to maintain skin oil levels, providing a proof of principle that other signaling pathways downstream of Krox20 could be therapeutic targets for SG-related diseases.
Authors
Yumeng Zhang, Pernelle Pulh, Michelle F. Pan, Yi He, Juanzhu Yan, Annie Li, Renée M. McKay, Lu Q. Le
×Abstract
Transmembrane protein 175 (TMEM175), implicated in Parkinson’s disease (PD) risk, has been variably proposed to function as a background K+ “leak” channel or a proton-activated proton channel in lysosomes. Here, we identified the rare TMEM175 variant p.L275R in a patient with early onset PD. Electrophysiological analyses revealed that TMEM175-L275R mutant proteins retain normal lysosomal expression and K+ “leak” activity, but specifically lose proton- and agonist-dependent activation gating. In skin fibroblasts isolated from the patient with PD harboring the monoallelic p.L275R mutation (TMEM175+/L275R), and in derived induced pluripotent stem cells and induced dopaminergic neurons, lysosomal H+ flux, acidification, and degradation were impaired. These lysosomal defects were corrected upon genome editing to produce the isogenic WT allele (+/+Cor), but appeared when the mutant allele was introduced onto a WT background (+/L275RMut). Pathological α-synuclein aggregation was facilitated in patient-derived (+/L275R) and mutation-introduced (+/L275RMut) neurons. Consistent with these genetic findings, pharmacological activation of TMEM175 with small-molecule agonists restored lysosomal functions and reduced α-synuclein aggregation in TMEM175+/L275R neurons. In in-vivo studies, equivalent-site–mutation knock-in mice demonstrated synucleinopathy and PD-like motor phenotypes. Collectively, our work provides genetic and pharmacological evidence that severe loss-of-function mutations may contribute causally to the onset age and pathogenesis of PD and identifies lysosomal proton channels and transporters as potential therapeutic targets for PD intervention.
Authors
Xiaotong Yang, Ping Li, Man Lv, Lingyong Wang, Ruyi Shan, Zikai Jiang, Danzhen Chen, Fangqian Huang, Weijie Cai, Liding Zhao, Zuoyou Guo, Xinhui Chen, Zhidong Cen, Yichang Wang, Wei Yang, Xinran Li, Wei Luo, Lin Yang, Meiqin Hu, Haoxing Xu
×Abstract
Regulatory T cells (Tregs) hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Tregs in both a mouse model of MS and patients with MS exhibited a preferential susceptibility to receptor-interacting serine/threonine kinase 1–dependent (RIPK1-dependent) necroptosis. Mechanistically, a FOXP3-driven, low-glucose metabolic program rendered Tregs intrinsically susceptible to necroptosis by limiting O-GlcNAcylation (O-GlcNAc) modification on RIPK1. This vulnerability was not shared by conventional T cells under comparable inflammatory conditions. Finally, in combination with adoptive Treg transfer, we show that selective inhibition of necroptosis in Tregs enhanced their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Tregs for the treatment of autoimmune diseases.
Authors
Qiaoyan Wu, Na Cui, Li Gao, Zhihui Lu, Xiang Ao, Rui Pang, Xingyan Li, Heling Pan, Daichao Xu, Peiying Li, Junying Yuan, Chengyu Zou
×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
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Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is driven by aberrant expression of the early embryonic transcription factor Double Homeobox 4 (DUX4), yet the mechanisms linking low, sporadic DUX4 activity to progressive muscle degeneration remain unclear. Here, we identify cellular senescence as a central and early mechanism in FSHD pathogenesis. Analysis of patient muscle transcriptomes revealed strong enrichment of senescence and senescence-associated secretory phenotype (SASP) programs that correlated with DUX4 activity, clinical severity, and histopathological changes. Notably, these signatures were detectable even in STIR-negative muscles, defining a prodystrophic state characterized by early molecular alterations preceding overt MRI-detectable inflammation and highlighting their potential utility as early biomarkers of disease activity. Using an FSHD mouse model, we show that DUX4-induced muscle injury rapidly triggers senescence, which then progressively expands. Fibroadipogenic progenitors and macrophages emerged as the principal senescent populations and key sources of pro-inflammatory and profibrotic SASP signals. Importantly, senescence was therapeutically modifiable. Treatment with the nucleoside reverse transcriptase inhibitor lamivudine (3TC), which inhibits LINE-1 reverse transcriptase activity, significantly reduced senescence, inflammation, and fibrosis while promoting muscle regeneration. These findings identify cellular senescence as a tractable driver of FSHD and warrant senotherapeutic strategies, particularly lamivudine, for clinical intervention in FSHD.
Authors
Usuk Jung, Erdong Wei, Ana Mitanoska, Philipp Heher, Kenric Chen, Haseeb Ahsan, Xu Zhang, Giorgio Tasca, Paul D. Robbins, Nathan K. LeBrasseur, Michael Kyba, Darko Bosnakovski
Abstract
Deciphering immune privilege at the maternal-fetal interface is essential for understanding how reproductive success and host defense are simultaneously maintained. Decidualization, occurring within the specialized stromal tissue encapsulating the fetus and placenta, shapes local immune adaptation required for healthy pregnancy. Here, we identify a decidua-enriched effector-like memory CD8+ T cell subset marked by CD45RA in humans and CX3CR1 in mice. These cells preferentially accumulate in the decidua, which harbors a CX3CL1-dominant chemokine niche, and disruption of Cx3cr1 or uterine Cx3cl1 impaired their decidual recruitment and tissue localization. Human CD45RA+ and murine CX3CR1+ decidual memory CD8+ T cells shared conserved transcriptional and functional features, including enhanced cytotoxic potential and limited inflammatory cytokine production. Functionally, CX3CL1-mediated CD8+ T cell accumulation improved local control of prenatal Listeria monocytogenes infection and reduced infection-associated fetal loss. In contrast, fetal antigen-specific CD8+ T cell accumulation and fetal resorption occurred independently of uterine CX3CL1. Together, our findings define the maternal-fetal interface as an active immunological gatekeeper, that compartmentalizing CD8+ T cell-mediated antimicrobial adaptive immunity through the conserved CX3CL1-CX3CR1 axis, supporting pathogen-specific defense while preserving fetal tolerance.
Authors
Lu Liu, Xixi Huang, Tingxuan Yin, Xianyang Hu, Hailin Yu, Guohua Zhu, Chunfang Xu, Jiajia Chen, Jiangyuan Du, Hongyan Wang, Qingyu Wu, Wei Zhang, Feng Wang, Huimei Wu, Meirong Du
Abstract
Pathogenic SCN2A loss-of-function (LoF) variants can cause severe, refractory epilepsy with limited treatment options. Existing Scn2a-LoF mouse models exhibit few spontaneous seizures, limiting the dynamic range needed to assess therapeutic efficacy. We therefore generated gene-trap Scn2a-deficient mice on the seizure-prone DBA/2J background. These mice experienced hundreds of spontaneous absence seizures per day, characterized by concurrent behavioral arrest and EEG spike–wave discharges (SWDs). Partial restoration of Scn2a expression reduced seizure burden. Electrophysiological analysis revealed impaired action potential waveforms yet increased repetitive firing, alongside coordinated downregulation of voltage-gated potassium channel genes, potentially contributing to hyperexcitability. Given the broad potassium channel downregulation and prior efficacy of KCNA1 gene therapy in refractory seizure models, we selected KV1.1 as a potential therapeutic target and used a drug-controllable adeno-associated virus (AAV) to express human KCNA1. We found that this intervention normalized elevated neuronal firing and reduced spontaneous seizure burden in Scn2a-deficient mice. Extending these findings to a human cell-based platform, AAV-mediated KCNA1 expression also reduced neuronal firing in human cortical organoids carrying a SCN2A-truncating variant identified in patients. Together, these findings provide proof of principle for drug-controllable KCNA1 gene therapy as a promising treatment avenue for epilepsy related to SCN2A LoF variants.
Authors
Zaiyang Zhang, Jingliang Zhang, Xiaoling Chen, Brody A. Deming, Shivam Kant, Purba Mandal, Harish Kothandaraman, Phillip J. SanMiguel, Manasi S. Halurkar, Akila D. Abeyaratna, Morgan J. Robinson, Iuliia Vitko, Ronald P. Gaykema, Chongli Yuan, Nadia A. Lanman, Matthew T. Tegtmeyer, Dan Wang, Guangping Gao, Riyi Shi, Edward Perez-Reyes, Yang Yang
Abstract
In Type 1 Diabetes (T1D), disease onset and immunotherapy responses vary widely, reflecting heterogeneous stage-specific immune dysregulation that remains undefined. To investigate this heterogeneity, we engineered microporous polycaprolactone scaffolds that form synthetic immunological niches (INs) subcutaneously and capture tissue-associated systemic immune changes. Building on our prior demonstration of IN-based longitudinal T1D monitoring, we use multimodal IN profiling to define the immune changes underlying divergent disease trajectories and immunotherapy responses. In non-obese diabetic (NOD) mice, longitudinal transcriptomic profiling of IN identified early myeloid associated changes, followed by increasing T cell-associated dysregulation that distinguished progressors from non-progressors. An early-stage IN-based T1D gene signature stratified NOD progressors from non-progressors by 6 weeks of age and was conserved across human T1D tissues, distinguishing T1D from non-diabetic individuals in spleen and pancreatic lymph node samples, but not in peripheral blood. Signature-based stratification revealed macrophage-associated TNFα pathway enrichment in pancreas of NOD progressors, which was validated in human T1D islets. Given the heterogeneous response to anti-TNFα therapy, IN profiling identified genesets associated with anti-TNFα efficacy and generated a response score that prospectively distinguished treatment-sensitive from resistant mice. These findings establish IN as a platform for detecting stage-wise immune dysregulation and stratifying immunotherapy response in T1D.
Authors
Jyotirmoy Roy, Yifei Jiang, Runbo Mao, Jessica L. King, Amod Talekar, Donglin Liu, Lillian Holman, Haoxuan Zeng, Xin Luo, Laila M. Rad, Peter Sajjakulnukit, Brianna Ha, Kai Liu, Elizabeth J. Bealer, Bryan Wonski, Kathryn Kang, Sean T. Carey, Luke F. Bugada, Brooke M. Smiley, Shahzad Sohail, Antonio D. Holmes, Dominik Awad, Aaron H. Morris, Costas A. Lyssiotis, Jie Liu, Lonnie D. Shea
Abstract
Commonly viewed as a negative prognostic factor in cancer, obesity is associated with improved responses to cancer immunotherapy using immune checkpoint inhibitors (ICIs). Although data suggest a sexual dimorphism influencing the effects of obesity on immunotherapy responses, to our knowledge, the intersection of sex and obesity on immunotherapy requires further exploration. We demonstrate, in a pan-cancer analysis stratified by sex and BMI, that obesity (BMI ≥ 30) is associated with improved survival after ICI only in male patients. In preclinical models of diet-induced obesity (DIO), we observed that only DIO male tumor-bearing mice responded better to ICI. The differential effect of sex on outcomes was associated with alterations in the tumor microenvironment where DIO female mice demonstrated increased tumor-associated macrophages skewed toward a M2 phenotype. Ovariectomy of DIO female mice reduced M2 polarization and increased anti-tumor immune responses including increases in tumor-infiltrating T cells following ICI. Metabolomic analysis of DIO mice demonstrated distinct profiles base on sex. Re-stratification of female cancer patients revealed that obesity was associated with improved outcome, but only in post-menopausal (age ≥ 55) patients. We identify that the immunotherapy “obesity paradox” is sex-dependent and that hormonal and metabolomic status modulates the influence of obesity on ICIs.
Authors
Logan V. Vick, Spencer R. Rosario, Ziming Wang, Craig Collins, Lam T. Khuat, Yatian Yang, Michael K. Sheng, Wahed A. Firoz, Ryan N. Nielsen, Yao-Hui Sun, Aryana M. Razmara, Hossein Borghaei, Emmanuel S. Antonarakis, Andrew Elliott, Nishant Gandhi, Raid Aljumaily, Sami Ibrahimi, Michael Machiorlatti, Sara K. Vesely, Shuchi Gulati, Sarbajit Mukherjee, Robert J. Canter, Sean J. Judge, Arta M. Monjazeb, William J. Murphy
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Series edited by Rinath Jeselsohn
Emerging therapeutic strategies in breast cancer
Series edited by Rinath Jeselsohn
Breast cancer is the most common cancer in women worldwide, with more than 2 million women diagnosed each year. This series of reviews, curated by Dr. Rinath Jeselsohn, highlights recent breakthroughs in therapeutic development that are changing the outlook for breast cancer patients, including improvements in immunotherapy, antibody-drug conjugates, endocrine therapies, and kinase inhibitors.
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)