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<p>Intracerebral haemorrhage (ICH) is a subtype&#xa0;of stroke, with resulting long-term disability determined by secondary brain injury. The prevailing biphasic model of neuroinflammation, which conceptualizes a temporal transition from acute to chronic stages, fails to reconcile persistent clinical trial failures or to explain the mechanisms underpinning the progression to chronic neurological deficits. We propose that the core pathology is the failure of acute inflammation to resolve in a timely manner owing to a functional collapse of physiological pro-resolution programmes, governed by dysregulation at critical molecular checkpoints&#xa0;such as the USP11–p53 axis. This failure locks the microenvironment into a destructive, non-resolving state, perpetuating immune-mediated damage. We discuss the evidence for a causal link between this checkpoint failure and the defining chronic sequelae: progressive white matter injury, inhibitory gliosis and large-scale network disconnection. We conceptualize the long-term motor, cognitive and affective impairments as a cohesive clinical entity, which we term post-ICH sequelae. This framework calls for a therapeutic reorientation from broad immunosuppression towards precision pro-resolution strategies such as USP11 inhibitors guided by biomarker-based immune staging. This Perspective provides a theoretical foundation, currently supported predominantly by preclinical evidence, and a translational roadmap for improving long-term recovery after ICH.</p>

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Failed resolution of inflammation in intracerebral haemorrhage

  • 期刊论文

  • 发表日期：

    2026年6月23日

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  • Liang Cao,
  • Wang Zhao,
  • Yanjun Zhang,
  • Wenjun Pi,
  • V. Wee Yong,
  • Mengzhou Xue

摘要

Intracerebral haemorrhage (ICH) is a subtype of stroke, with resulting long-term disability determined by secondary brain injury. The prevailing biphasic model of neuroinflammation, which conceptualizes a temporal transition from acute to chronic stages, fails to reconcile persistent clinical trial failures or to explain the mechanisms underpinning the progression to chronic neurological deficits. We propose that the core pathology is the failure of acute inflammation to resolve in a timely manner owing to a functional collapse of physiological pro-resolution programmes, governed by dysregulation at critical molecular checkpoints such as the USP11–p53 axis. This failure locks the microenvironment into a destructive, non-resolving state, perpetuating immune-mediated damage. We discuss the evidence for a causal link between this checkpoint failure and the defining chronic sequelae: progressive white matter injury, inhibitory gliosis and large-scale network disconnection. We conceptualize the long-term motor, cognitive and affective impairments as a cohesive clinical entity, which we term post-ICH sequelae. This framework calls for a therapeutic reorientation from broad immunosuppression towards precision pro-resolution strategies such as USP11 inhibitors guided by biomarker-based immune staging. This Perspective provides a theoretical foundation, currently supported predominantly by preclinical evidence, and a translational roadmap for improving long-term recovery after ICH.