Curing the brain: in search for new astrocyte-specific therapies

www.nature.com/emm REVIEW ARTICLE OPEN Curing the brain: in search for new astrocyte-specific therapies ✉ ✉ Alexei Verkhratsky1,2,3,4,5 , C. Justin Lee 6 , Heejung Chun 7, Christian Göritz 8,9, Tibor Harkany10,11, Jae-Hun Lee 6, 6 12 Sangkyu Lee , Maria Lindskog , Wuhyun Koh 6, Jan Mulder11, Min-Ho Nam 13, Ole Petter Ottersen14,15,16, Marcela Pekna17, Milos Pekny17, Aleksandra Pękowska18, Hoon Ryu13, Chang Ho Sohn19, Evgenii O. Tretiakov10, Verena Untiet 20, Tim J. Viney21, ✉ ✉ Wongu Youn 6, Chenju Yi22, Robert Zorec4,23, Mijin Yun24, Eunji Cheong25 and Agneta Nordberg26,27 1234567890();,: © The Author(s) 2026, modified publication 2026 Astroglia, an extended class of homeostatic and defensive cells of the central nervous system (CNS), contribute to the pathogenesis of all known neurological and neuropsychiatric disorders. The pathophysiology of astrocytes is complex, mutable, disease and diseasestage specific. In neuroinflammatory lesions and in various chronic conditions, astrocytes undergo an evolutionary conserved defensive remodeling known as reactive astrogliosis, which produces highly heterogeneous reactive astrocytic phenotypes. Broadly, reactive astrogliosis can be classified into proliferative anysomorphic barrier-forming astrogliosis characteristic of traumatic CNS lesions and nonproliferative isomorphic gliosis widely manifested in chronic neuropathologies. In addition, in many pathologies, astrocytes undergo atrophy and asthenia with resulting loss of homeostatic support and neuroprotection precipitating neuronal damage. Reactive and atrophic astrocytes may coexist or emerge in sequence in a disease-stage-dependent manner. Several classes of astrocyte-specific molecules and processes implicated in various diseases of the CNS represent therapeutic targets. Astrocyte-specific therapeutic strategies may improve both disease-preventing and disease-modifying therapeutic outcomes. Experimental & Molecular Medicine (2026) 58:1086–1127; https://doi.org/10.1038/s12276-026-01712-4 FROM NEURONOCENTRISM TO THE INCLUSIVE BRAIN—THE KEY FOR THERAPEUTIC SUCCESS Cognitive impairments are caused by many pathologies affecting the ability to think, concentrate, remember or make decisions. Diseases of the brain, which lead to cognitive and neurological deficiencies and limit the quality of life in the aging global population, represent the main therapeutic challenge of the twenty-first century. There are no effective therapeutic strategies for most of the major disorders of the brain, including ischemic, toxic, autoimmune, neurodevelopmental, neuropsychiatric, malignant and neurodegenerative pathologies; for many of these, neither disease-preventing nor disease-modifying medicines exist. This reflects the complexity of the human nervous system forged by ~500 million years of evolution, which assembled 200 billion of highly heterogeneous cells into intricate networks capable of lifelong structural and functional plasticity. The brain cells include executive neurons capable of long-range fast signaling connecting the brain to the body, the homeostatic and defensive neuroglia, and cells of the brain vasculature. The segregation of functions between neurons and neuroglia emerged early in evolution1. Invertebrates possess many types of neuroglial cells that create brain–body barriers, protect and support axons, and produce complex defensive responses to external insults. In vertebrates and mammals, neuroglia underwent further advancement, becoming the main element responsible for nervous tissue homeostasis and protection. The human central nervous system (CNS) contains three main types of neuroglia: the homeostatic and neuroprotective astroglia, 1 Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. 2International Joint Research Centre on Purinergic Signalling of Sichuan Province Chengdu University of Traditional Chinese Medicine, Chengdu, China. 3Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Guangdong, China. 4Celica, BIOMEDICAL, Ljubljana, Slovenia. 5Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China. 6Center for Memory and Glioscience, Institute for Basic Science, Daejeon, Republic of Korea. 7Collage of Pharmacy, Yonsei-SL Institute, Yonsei University, Incheon, Republic of Korea. 8Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden, Stockholm, Sweden. 9Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, Hong Kong. 10Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria. 11Department of Neuroscience, Karolinska Institutet, Solna, Sweden. 12Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. 13Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. 14Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 15Oslo New University College, Oslo, Norway. 16Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 17Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. 18Dioscuri Centre for Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. 19Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. 20Division of Astrocyte Driven Ionostasis, Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark. 21Department of Pharmacology, University of Oxford, Oxford, UK. 22Department of Geriatrics, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China. 23Institute of Pathophysiology, Laboratory of Neuroendocrinology and Molecular Cell Physiology, University of Ljubljana, Ljubljana, Slovenia. 24Department of Nuclear Medicine, Yonsei Univserity College of Medicine, Seoul, Republic of Korea. 25Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. 26Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska institutet, Stockholm, Sweden. 27Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden. ✉email: ; ; ; Received: 1 October 2025 Revised: 7 January 2026 Accepted: 14 January 2026 Published online: 24 April 2026 A. Verkhratsky et al. 1087 Fig. 1 Classification of astroglia. The plates show diff feremt types of astroglial cells with typical morphology. the myelinating oligodendroglia and the defensive microglia2–7. All cells in the brain are linked by multiple feedforward and feedback connections, which maintain the function, versatility and plasticity of the neural tissue8 (...truncated)