Cerebral small vessel disease (CSVD) refers to a series of disorders mainly affecting the small arteries, arterioles, venules, and capillaries of the brain. Its neuroimaging features include recent small subcortical infarcts, lacunes, white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy. Clinically, CSVD commonly manifests as cognitive impairment, dementia, and executive dysfunction (Jacob et al., 2023). CSVD accounts for approximately 25 % of all strokes and contributes to about 45 % of dementia cases. Its prevalence increases markedly with age, affecting nearly 5 % of individuals in their 50 years and approaching almost 100 % in those over 90 years old (Cannistraro et al., 2019).

Recent treatment mainly focuses on the control of risk factors, such as antihypertensive drugs, or the alleviation of cognitive deficits by using cholinesterase inhibitors (Donepezil, Galantamine) and N-methyl-D-aspartate (NMDA) receptor antagonists (Memantine) (Zanon Zotin et al., 2021). However, the effectiveness of current treatment strategies for CSVD remains limited, primarily because they are unable to reverse the microvascular damage and white matter lesions (Wardlaw et al., 2019). Evidences from recent studies indicate that available pharmacological interventions offer only modest benefits in improving cognitive function and do not specifically target the underlying pathophysiological mechanisms of CSVD (Cannistraro et al., 2019). Moreover, most existing therapies are short-term symptom-based approaches, lacking robust evidence for long-term efficacy or significant impact on patients' quality of life (Hamilton et al., 2021; Gao et al., 2022).

Ginkgo biloba L. is one of the most widely used traditional medicinal plants and is listed in the Pharmacopoeia of the People's Republic of China. It has been cultivated and applied medicinally for thousands of years in countries such as China, Japan, and Korea. The medicinal part is the dried leaf, first recorded in ancient Chinese texts such as the Shennong's Classic of Materia Medica. In modern clinical practice, Ginkgo biloba is commonly used as an adjunct treatment for neurological and cardiovascular-cerebrovascular diseases, including Alzheimer's disease (Nowak et al., 2021), dementia (Tomino et al., 2021), and ischemic stroke (Chong et al., 2020).The plant contains a variety of chemical constituents, mainly flavonoids, terpenoids, organic acids, and polyphenols (Liu et al., 2021), which contribute to its antioxidant (Singh et al., 2019), anti-inflammatory (L. Zhang et al., 2023), anti-apoptotic (Cao et al., 2022), antiplatelet aggregation (Zhang et al., 2024), and neuroprotective activities (Liu et al., 2024). Standardized Ginkgo biloba preparations, such as EGb 761, have been approved for clinical use in several countries and are included in multiple national pharmacopoeias. Ginkgo biloba extract 50 (GBE50), a fifth-generation standardized extract developed in China, features improved stability and higher content of active flavonoids and terpenoids.

Pharmacological studies have shown that GBE50 exhibits strong antioxidant (Liang et al., 2024), anti-inflammatory (Liu et al., 2018), and vascular-protective effects (Ke et al., 2021), which are closely related to the pathogenesis of CSVD. Recent findings suggest that GBE50 may improve the integrity of the neurovascular unit, enhance cerebral perfusion, and reduce neuroinflammation, thereby contributing to the improvement of cognitive deficits (Yu et al., 2025). These multitarget pharmacological effects highlight the therapeutic potential of GBE50 in the management of CSVD. However, systematic research on the therapeutic mechanisms of GBE50 in CSVD remains limited. In particular, evidence regarding its effects on mitochondrial protection, anti-apoptosis, oxidative stress regulation, and white matter integrity is insufficient. In this study, we used bilateral carotid artery stenosis (BCAS) model mice and network pharmacology combined with molecular detection to show that GBE50 might be a new strategy for treatment of cognitive impairment related to CSVD.

The full names and abbreviations used throughout this article are listed in Table 1.