Journal Article Review Epublish
PubMed: 40813983 DOI: 10.1186/s12974-025-03526-z
Cystatin F-a key player in central nervous system disease.
J Neuroinflammation 22(1):203
Authors: Yi-Ting Wang, Qiang Li, Jun-Chao Liu, Chen Chen, He-Xuan Ding, Xu Zha, Ke Zhang
Affiliations
- Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, 110122, China.
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, 110000, China.
- The Research Center for Medical Genomics, Key Laboratory of Cell Biology, National Health Commission of the PRC and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, China Medical University, Shenyang, 110122, China.
- Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, 110122, China.
Abstract
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.
MeSH
Microglia, Sclerosis, Central Nervous System Diseases, Central Nervous System, Therapeutics, Nervous System, Nervous System Diseases, Cystatins