Ferroptosis in vascular cognitive impairment: pathological mechanisms and traditional Chinese medicine interventions

Vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits arising from cerebrovascular disease, representing a major cause of dementia worldwide. Ferroptosis, a recently identified form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a potential contributor to neuronal and glial cell injury in cerebrovascular pathologies, although direct evidence in VCI itself remains limited. Traditional Chinese medicine (TCM) has demonstrated promising neuroprotective effects, with growing evidence suggesting that its therapeutic benefits may partly involve the modulation of ferroptosis pathways.

This narrative review aims to comprehensively summarize the pathological mechanisms of ferroptosis in VCI, elucidate the molecular crosstalk between ferroptotic cascades and cerebrovascular injury, and highlight the therapeutic potential of TCM interventions targeting ferroptosis in VCI.

A comprehensive literature search was conducted across PubMed, Web of Science, and CNKI databases for publications from January 2019 to June 2026 (final search performed on 15 April 2026), using predefined terms related to ferroptosis, vascular cognitive impairment, cerebrovascular disease, and traditional Chinese medicine; the full search strategy and evidence-classification scheme are described in Section 1.1.

Preclinical evidence suggests that ferroptosis may contribute to VCI pathogenesis through multiple mechanisms, including iron overload-mediated oxidative damage, glutathione depletion, lipid peroxidation, blood-brain barrier disruption, neuroinflammation, and white matter injury. Several TCM compounds and formulas, including baicalein, salvianolic acid B, gastrodin, astragaloside IV, and Buyang Huanwu Decoction, have demonstrated anti-ferroptotic effects in experimental models through modulation of GPX4, Nrf2/HO-1, System Xc-, and iron metabolism pathways. These preclinical findings provide a preliminary mechanistic basis for the neuroprotective effects of TCM in VCI, although direct clinical evidence is still lacking.

Targeting ferroptosis represents a potential therapeutic strategy for VCI, and TCM offers a rich repository of multi-target, multi-pathway anti-ferroptotic agents. However, most supporting evidence is derived from related cerebrovascular or non-neurological models rather than from VCI itself. Future research should prioritize VCI-specific mechanistic studies, rigorous validation of ferroptosis-specific effects, and clinical translation of TCM-mediated ferroptosis regulation.