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<p>Cystatin F is an endogenous cysteine protease inhibitor that belongs to the type II cystatin family. It has several unique characteristic structures that determine some of its specific functions. Cystatin F is expressed predominantly in peripheral immune cells and in the microglia of the central nervous system (CNS). Under physiological conditions, the expression of cystatin F in the CNS is minimal. However, emerging evidence suggests that it is significantly upregulated in several CNS diseases. Intriguingly, the role of cystatin F differs across disease contexts—serving a neuroprotective function while promoting pathological progression. Moreover, its function may shift across different pathological stages within the same disorder, reflecting a multifaceted pathophysiology. Cystatin F primarily acts by modulating neuroinflammation, clearing debris, and orchestrating immune responses via its selective expression in disease-associated microglia. As a vital player in CNS diseases, various intervention strategies targeting cystatin F have been proposed, including receptor-interacting protein kinase 1 pathway inhibition, miRNA targeting, mRNA stabilization, necroptosis inhibition, transcriptional regulation and upstream pathway modulation. Several approaches have yielded encouraging results in preclinical models, underscoring the therapeutic potential of modulating cystatin F activity. This review provides a comprehensive overview of the structural features, biological functions, and diverse roles of cystatin F in CNS diseases, including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, Aicardi–Goutières syndrome, prion disease, and glioblastoma. Recent advances in therapeutic interventions focusing on cystatin F have been critically assessed, and key challenges related to clinical translation are outlined, offering new perspectives on therapeutic directions.</p>

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Cystatin F-a key player in central nervous system disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月14日

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  • Yi-Ting Wang,
  • Qiang Li,
  • Jun-Chao Liu,
  • Chen Chen,
  • He-Xuan Ding,
  • Xu Zha,
  • Ke Zhang

摘要

Cystatin F is an endogenous cysteine protease inhibitor that belongs to the type II cystatin family. It has several unique characteristic structures that determine some of its specific functions. Cystatin F is expressed predominantly in peripheral immune cells and in the microglia of the central nervous system (CNS). Under physiological conditions, the expression of cystatin F in the CNS is minimal. However, emerging evidence suggests that it is significantly upregulated in several CNS diseases. Intriguingly, the role of cystatin F differs across disease contexts—serving a neuroprotective function while promoting pathological progression. Moreover, its function may shift across different pathological stages within the same disorder, reflecting a multifaceted pathophysiology. Cystatin F primarily acts by modulating neuroinflammation, clearing debris, and orchestrating immune responses via its selective expression in disease-associated microglia. As a vital player in CNS diseases, various intervention strategies targeting cystatin F have been proposed, including receptor-interacting protein kinase 1 pathway inhibition, miRNA targeting, mRNA stabilization, necroptosis inhibition, transcriptional regulation and upstream pathway modulation. Several approaches have yielded encouraging results in preclinical models, underscoring the therapeutic potential of modulating cystatin F activity. This review provides a comprehensive overview of the structural features, biological functions, and diverse roles of cystatin F in CNS diseases, including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, Aicardi–Goutières syndrome, prion disease, and glioblastoma. Recent advances in therapeutic interventions focusing on cystatin F have been critically assessed, and key challenges related to clinical translation are outlined, offering new perspectives on therapeutic directions.