Decoding spontaneous intracerebral hemorrhage: mechanistic breakthroughs and disruptive revolution in pharmacological treatment

www.nature.com/emm REVIEW ARTICLE OPEN Decoding spontaneous intracerebral hemorrhage: mechanistic breakthroughs and disruptive revolution in pharmacological treatment ✉ ✉ ✉ Yisheng Chen 1,2,3,4,15, Guanghui Wu1,15, Wangzheqi Zhang5 , Zui Zou5 , Lei Huang4 , Haojun Shi6, Qiangqiang Wang 7, ✉ ✉ 8 9 10 11 12 13 ✉ Weijian Chen , Zhiwen Luo , Zhijie Zhao , Li Wu , Zhiwei Li , Jianhua Peng , Yujie Chen 14 and John H. Zhang2,3,4 1234567890();,: © The Author(s) 2026 Spontaneous intracerebral hemorrhage (ICH), especially hypertensive basal ganglia hemorrhage, is a severe, often fatal stroke subtype with high morbidity and mortality. This historical review traces therapeutic progress from the 1960s to the present, emphasizing rehabilitation, peripheral–central nervous system interactions, and clinical outcomes. Molecular mechanisms, early treatments, and advances in interventions are examined. Rehabilitation strategies, such as exercise programs, stem cell therapies, and novel physical modalities, are evaluated for their effects on neuroprotection, neuroplasticity, and functional recovery. Pharmacological approaches during subacute and chronic phases are also reviewed. Clinical trials (phases I–III) are critically assessed for end points and efficacy of combined therapies. This Review highlights emerging paradigms targeting peripheral–central pathways, personalized rehabilitation, and future directions, while addressing research limitations and clinical challenges. Experimental & Molecular Medicine (2026) 58:1394–1408; https://doi.org/10.1038/s12276-026-01733-z Graphical Abstract Evolution of treatment strategies for intracerebral hemorrhage (ICH). a, Development of treatment drugs for intracerebral hemorrhage. Since the 1990s, pharmacological interventions have evolved, including thrombolytics, anticoagulants, cell-protective drugs, ferroptosis inhibitors, natural medicines, and hydrogen therapy, all aimed at improving patient outcomes. b, Advancements in drug treatments for ICH. Recent therapeutic innovations focus on reducing ICH-related damage, including the use of tranexamic acid for hemorrhage control, ferroptosis inhibitors for preventing delayed cerebral ischemia, and hydrogen therapy to mitigate inflammatory and oxidative stress responses. c, Application of rehabilitation therapy in ICH. Rehabilitation strategies, including physical therapy and pharmacological support, promote functional recovery by enhancing limb function, balance, and coordination while reducing inflammatory responses and accelerating neuroplasticity. d, Traditional treatment methods for ICH. Various traditional Chinese medicine approaches, such as Salvia miltiorrhiza-based adjuvant therapy, acupuncture for blood circulation enhancement, Tuina therapy, and hypothermia treatment, contribute to reducing cell apoptosis and brain edema. e, Current status of clinical trials. Ongoing trials assess drug safety, efficacy, and application across different patient populations, whereas challenges such as patient variability, drug dosage optimization, and administration timing remain crucial for translating research into clinical practice. f, Future prospects. The integration of multidimensional treatment approaches, encompassing gene therapy, exosome therapy, nanotechnology-based drug delivery, hydrogen 1 Fujian Key Laboratory of Toxicant and Drug Toxicology, undefined, Department of Vascular and Interventional Radiology, Ningde Municipal Hospital of Fujian Medical University, Ningde Normal University, Ningde, China. 2Department of Neurosurgery, School of Medicine, Loma Linda University, Loma Linda, CA, USA. 3Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA, USA. 4Department of Neurosurgery and Anesthesiology, School of Medicine, Loma Linda University, Loma Linda, CA, USA. 5School of Anesthesiology, Naval Medical University, Shanghai, China. 6Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China. 7Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 8 Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. 9Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China. 10 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 11Kunming University of Science and Technology, Chenggong Campus, Kunming, People’s Republic of China. 12Clinical Laboratory Center, The People’s Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China. 13Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China. 14Neurosurgical Intensive Care Unit, Department of Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. 15These authors contributed equally: Yisheng Chen, Guanghui Wu. ✉email: ; ; ; ; ; ; Received: 28 August 2025 Revised: 25 February 2026 Accepted: 26 February 2026 Published online: 28 May 2026 Y. Chen et al. 1395 therapy, and the combination of modern pharmacology with traditional medicine, holds significant promise for refining rehabilitation protocols and enhancing patient outcomes. INTRODUCTION Spontaneous intracerebral hemorrhage (ICH) is one of the most devastating types of stroke, affecting nearly two million individuals worldwide each year. Despite advances in emergency medicine and neurocritical care, early mortality remains high, and many survivors continue to experience long-term impairments1. Unlike traumatic hemorrhage that arises from external mechanical injury, spontaneous ICH typically results from intrinsic vascular pathology such as chronic hypertension, cerebral small vessel disease, or the use of anticoagulants1. The pathophysiology of ICH is commonly divided into primary and secondary brain injury. Primary injury is caused by the immediate mass effect of the hematoma, leading to compression, ischemia, and mechanical destruction of surrounding brain tissue2. Secondary injury evolves over hours to days and exerts a stronger impact on long-term outcomes. It involves multiple processes including the breakdown of red blood cells, release of hemoglobin and iron, disruption of the blood–brain barrier (BBB), oxidative stress, neuroinflammation, and various forms of programmed cell death3. Among these mechanisms, iron overload and ferroptosis, which is an iron-dependent form of cell death characterized by lipid peroxidation, have been recognized as central contributors to perihematomal edema and progressive neuronal loss. Clinically, ICH is characterized by the sudden onset of focal neurological deficits that may rapidly progress to coma or death. CT remains the gold standard for diagnosis because it enables rapid localization of the hematoma, assessment of hematoma volume, and detection (...truncated)