Cuproptosis in Cerebrovascular Diseases: Mechanisms and Advances in Targeted Therapeutic Strategies.

Authors

Xinyi Zhang, Rufan Xu, Hongrui Zhang, Ying Gao, Zhenhong Liu

Published in

Brain research bulletin. Pages 112120. Sep 17, 2026. Epub Sep 17, 2026.

Abstract

Cuproptosis is a recently identified form of regulated cell death. It is primarily driven by abnormal mitochondrial copper accumulation. Ferredoxin 1-dependent copper reduction promotes the pathological aggregation of lipoylated proteins involved in the tricarboxylic acid cycle and the loss of iron-sulfur cluster proteins. This process induces proteotoxic stress, ultimately causing the collapse of mitochondrial energy metabolism. Evidence from transcriptomic analyses, single-cell multi-omics studies, and in vivo and in vitro models suggests that copper dyshomeostasis may be involved in cerebrovascular disease. Specifically, it may contribute to oxidative stress, neuroinflammation, blood-brain barrier disruption, and neurovascular unit dysfunction in conditions including acute ischemic stroke, hemorrhagic stroke, vascular cognitive impairment, and cerebral small vessel disease. This review outlines the regulatory networks governing cerebral copper homeostasis, summarizes the molecular machinery of cuproptosis, and examines its crosstalk with apoptosis, pyroptosis, ferroptosis, and disulfidptosis. We discuss the potential molecular pathways by which cuproptosis may contribute to cerebrovascular injury, its possible role in modulating the local immune microenvironment, and emerging interventional strategies. Furthermore, we critically evaluate current therapeutic approaches and weigh their preclinical progress in light of current empirical limitations. Finally, we assess the translational potential and practical challenges of targeted nanomedicine platforms. By synthesizing these findings, this review provides a hypothesis-generating framework for future mechanistic and interventional research. These insights highlight the need for mechanistic validation, cuproptosis-specific biomarkers, and direct cerebrovascular efficacy and safety studies before clinical translation.

PMID:
42754178
Bibliographic data and abstract were imported from PubMed on 18 Sep 2026.

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