Cardiovascular disease (CVD) prevails as a leading cause of death worldwide, which has become a significant public health concern. According to epidemiological surveys, nearly one-third of global deaths can be attributed to CVD annually (Y. Jiang et al., 2022). Moreover, the incidence, prevalence, and mortality of CVD will continue to elevate given the increased aging population (W. Yu et al., 2022; Y. X. Zhou et al., 2021). Atherosclerosis, the formation of fatty and fibrous lesions in the intima layer of arteries, is recognized as the pathological basis and the predominant cause of CVD (Kong et al., 2022). Therefore, developing effective therapeutic intervention strategies against atherosclerosis is pivotal for CVD prevention and management.

Atherosclerosis is a complex pathologic process involving various cellular and molecular events, and endothelial dysfunction has been regarded as a critical and initiating factor in the pathogenesis of atherosclerosis (Libby, 2021). Endothelial cells (ECs), an integral component of the cardiovascular system, are arranged in a monolayer that constitutes the inner cellular lining of the blood vessels (Trimm & Red-Horse, 2023). ECs not merely serve as a barrier between blood and tissues but also exert much broader physiological functions, including regulating vascular tone, mediating mechanotransduction, repairing vascular injury, and secreting antiplatelet and anticoagulant molecules (Gimbrone Jr. & García-Cardeña, 2016; S. Xu et al., 2021). However, vascular endothelium dysfunction is mechanistically associated with various diseases, especially atherosclerosis and its complications (Gimbrone Jr. & García-Cardeña, 2016; S. Xu et al., 2021). During atherosclerosis initiation, exposure to pro-atherogenic factors interferes with the physiological activity of ECs, causing non-adaptive alterations in their functional phenotype and the occurrence of endothelial dysfunction (Akhtar & Sharma, 2022). The pro-atherogenic stimuli causing endothelial dysfunction include hypercholesterolemia, inflammation, oxidative stress, metabolic disorder, hypertension, sex hormonal dysregulation, aging, and hemodynamic forces (Gimbrone Jr. & García-Cardeña, 2016). Dysfunctional ECs promote the subendothelial retention of lipoproteins and induce the recruitment of circulating monocytes into the intima, provoking pathophysiological cascades that fuel the development of atherosclerosis (Akhtar & Sharma, 2022). Given the key roles of endothelial dysfunction in atherosclerosis, clinical assessment of endothelial function can help diagnose CVD and analyze potential cardiovascular risk (Gimbrone Jr. & García-Cardeña, 2016; S. Xu et al., 2021). Besides, many clinically used CVD drugs have been demonstrated to have endothelium-protective function, which contributes to their cardioprotective effects. (S. Xu et al., 2021). Therefore, targeting endothelial dysfunction holds great promise for preventing and treating atherosclerosis.

Despite advances in the development of therapeutics for atherosclerosis, the global burden of CVD remains unacceptably high (Rui et al., 2021). Thus, it is urgent to explore novel therapeutics to combat atherosclerosis. Natural products of plant origin constitute the most abundant source for discovering novel chemical entities for therapeutic use and developing new and more potent pharmaceuticals. With the advantages of low cost and high-level safety, natural compound-based therapies have been used for promoting human health for thousands of years and are currently receiving increased attention. Flavonoids represent a large group of polyphenolic compounds ubiquitously present in plant-based foods, teas, wines, and traditional herbal remedies (Fan et al., 2022). Structurally, these natural molecules possess a 15-carbon backbone (C6-C3-C6) with two aromatic rings (A and B rings) linked by one pyran ring (C ring) (Dias et al., 2021). Based on their carbon structure and the degree of oxidation, flavonoids can be classified into six subclasses: flavones, flavanones, flavanols, flavonols, isoflavones, and anthocyanins (Al-Khayri et al., 2022). Specifically, flavones represent a subclass that has a double bond between C2 and C3 in the flavonoid skeleton and possesses a ketone group on C4, while there is no substitution at the C3 position (Hostetler et al., 2017). Another flavonoid subclass flavanones share similar structure with flavones but differ only by having a saturated C ring (Panche et al., 2016). In contrast, flavanols are characterized by the absence of a double bond between C2 and C3 and the absence of a ketone group on C4, while featuring a hydroxyl group on C3 or C4 (Y. Luo et al., 2022). In addition, flavonols are the most ubiquitous flavonoids found in plants which possess a ketone group and a hydroxyl group on C3 (Daryanavard et al., 2023), and isoflavones, also known as phytoestrogens, feature a B ring connected to C3 position (Al-Khayri et al., 2022). Moreover, anthocyanins are also an important subfamily of flavonoids, which are polyhydroxylated and/or polymethoxylated glycosides derived from the 2-phenylbenzopyrilium ion (flavylium cation) (Arruda et al., 2021). Numerous studies have shown a broad spectrum of pharmacological properties of natural flavonoids, including anti-oxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic, and neuroprotective activities (Fan et al., 2022). In particular, flavonoids significantly benefit the cardiovascular system (Y. Liu et al., 2024). Based on epidemiological data, the intake of dietary flavonoids was associated with a lower risk of CVD (Parmenter et al., 2020). In animal models, flavonoids significantly attenuated the size of atherosclerotic plaque and reduced the levels of serum lipids and circulating pro-inflammatory factors, providing compelling evidence for the anti-atherosclerotic property of flavonoids (Liao et al., 2023). For a detailed overview of the effects of flavonoids against atherosclerosis, we refer to some recent reviews (Atrahimovich et al., 2021; Li, Wang, et al., 2022). In terms of the mechanisms of action, a plethora of flavonoids have been reported to target the endothelium and protect against vascular endothelial dysfunction, thereby exhibiting an atheroprotective potential (H. Li & Zhang, 2023; Li, Wang, et al., 2023; Yamagata & Yamori, 2020). In addition, many investigations have been conducted to unravel the signaling pathways/molecular targets mediating the endothelium-protective effects of flavonoids. These studies shed light on the promising potential of flavonoids as endothelial dysfunction-targeted therapeutic drugs for atherosclerosis management. In this review, we provide a comprehensive update on the latest research progress regarding the roles of natural flavonoids in regulating endothelial dysfunction and their potential therapeutic effects on atherosclerosis, emphasizing the underlying mechanisms. A total of 33 natural flavonoids widely found in plants and herbal medicines are included in this review, and their chemical structures are listed in Fig. 1. We aim to give novel insights into targeted therapy of atherosclerosis based on flavonoid-mediated endothelium protective mechanisms.