Secondary brain injury in spontaneous intracerebral hemorrhage: A narrative review of pathophysiological mechanisms, translational therapies, and future directions

Spontaneous intracerebral hemorrhage (ICH) remains a major cause of mortality and long-term disability worldwide. Brain injury after ICH reflects the combined effects of the primary mechanical damage caused by hematoma formation and a cascade of complex secondary injury mechanisms, including neuroinflammation, oxidative stress, iron-mediated toxicity, blood–brain barrier disruption, and microvascular dysfunction. Increasing knowledge of these pathophysiological pathways has led to the identification of several potential therapeutic targets. Multiple pharmacological strategies aimed at mitigating secondary brain injury have shown promising results in experimental models, although their translation into clinical benefit has remained limited. Nevertheless, recent advances in therapeutic technologies, neuroimaging, and biomarker research are opening new opportunities for accurate patient stratification and targeted therapeutic approaches within a precision medicine framework. In this review, we provide an updated overview of the mechanisms underlying secondary brain injury after spontaneous ICH and examine emerging therapeutic targets across both experimental and clinical research. We summarize the evidence from preclinical studies and clinical trials and discuss how recent technological and methodological advances may inform future translational strategies aimed at improving outcomes in patients with ICH.