Cellular and Molecular Mechanisms of Vascular Endothelial Injury Induced by Cigarette Smoke and Cigarette Smoke Extract in Atherosclerosis

Abstract

Although smoking is a well-recognized independent risk factor for atherosclerosis (AS), its core pathogenic mechanism lies in the induction of vascular endothelial cell (VEC) dysfunction, which represents the initial step of AS development. However, the mechanisms by which cigarette smoke (CS) and cigarette smoke extract (CSE) trigger and promote atherosclerotic progression via VECs remain incompletely understood. CS and CSE damage the vascular endothelial barrier through three key mechanisms: oxidative stress induction, inflammatory response activation, and endothelial cell apoptosis. This narrative review summarizes the cellular and molecular mechanisms by which CS and CSE disrupt vascular endothelial cell function through activation of the nuclear factor kappa B (NF-κB) signaling pathway, the nitric oxide (NO) synthesis pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway, based on experimental studies at the cellular and organ levels. This review aims to provide a novel perspective for clarifying the pathological basis of smoking-induced atherosclerosis and lay a foundation for the development of intervention strategies targeting endothelial protection.

Introduction

The World Health Organization’s (WHO) 2025 report underscores tobacco use as a paramount global health threat, driving 7 million annual premature deaths alongside widespread disability and chronic diseases.¹ CS exposure induces multisystem damage, particularly affecting the cardiovascular system: AS and coronary heart disease (CHD). Respiratory system: chronic obstructive pulmonary disease (COPD). Endocrine and metabolic system: diabetes mellitus. Reproductive system: prenatal defects and infertility. Oncogenesis: various carcinomas.^2–4 According to Centers for Disease Control and Prevention (CDC) data, smoking is recognized as a primary risk factor for cardiovascular disease (CVD). Compared to non-smokers, smokers have a two to four times higher risk of developing AS and CVD. Smoking induces vascular endothelial damage via three core mechanisms: oxidative stress, inflammatory activation, and apoptosis, ultimately accelerating AS progression.^4,5 While existing studies have established the smoking-AS pathogenesis connection, the precise cellular/molecular mechanisms underlying smoking-induced endothelial damage and subsequent AS development remain unclear. This review analyzes CS- and CSE-induced vascular endothelial injury, focusing on how these exposures contribute to AS pathogenesis through four core mechanisms: oxidative stress, inflammatory activation, apoptosis induction, and molecular pathway dysregulation. Although oxidative stress, inflammation, and apoptosis remain recognized as fundamental mechanisms underlying smoking-induced endothelial dysfunction, increasing evidence indicates that additional regulatory layers contribute to the progression of vascular injury. Recent advances have highlighted the importance of epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs such as microRNAs, in regulating endothelial inflammatory responses, oxidative homeostasis, and cellular senescence following cigarette smoke exposure. In parallel, emerging forms of regulated cell death, including pyroptosis and ferroptosis, have expanded our understanding of endothelial injury beyond classical apoptosis. Pyroptosis, characterized by inflammasome activation and gasdermin-mediated membrane disruption, links inflammatory signaling with endothelial cell death, whereas ferroptosis represents an iron-dependent cell death pathway associated with lipid peroxidation and redox imbalance. These emerging mechanisms may interact with conventional pathways, forming complex regulatory networks that accelerate endothelial dysfunction and atherosclerotic progression. Therefore, a comprehensive understanding of both classical and emerging mechanisms is essential for elucidating the pathological basis of smoking-related vascular disease. We also critically evaluate current therapies and propose future research directions, aiming to identify novel therapeutic targets for AS prevention and treatment.

This manuscript adopts a narrative literature review approach to summarize and discuss the mechanisms of cigarette smoke- and cigarette smoke extract-induced vascular endothelial injury and atherosclerotic progression. The data sources for this literature review included peer-reviewed journal articles, books, and authoritative reports from relevant databases such as PubMed, Web of Science, and Google Scholar. The databases were searched from their inception to March 2026. Keywords used for retrieval included cigarette smoke, cigarette smoke extract, vascular endothelial cell, oxidative stress, inflammation, apoptosis, and atherosclerosis. Priority was given to landmark original studies, mechanistic investigations and authoritative reviews highly relevant to the topic. As a narrative review rather than a systematic review, this work does not apply pre-registered strict inclusion/exclusion criteria or formal quality-of-evidence assessment, and the findings are presented as a descriptive synthesis.

Components and Effects of Cigarette Smoke and Its Extracts

Primary Active Ingredients and Effects

Cigarettes contain over 7,000 chemical compounds,^6,7 and some components exhibit vascular toxicity.^8,9 Notably, CS and CSE¹⁰ contain several important toxic constituents, including nicotine^9,11 and acrolein,¹² as well as tar¹³ a complex mixture of particulate-phase chemicals containing various toxic compounds, including polycyclic aromatic hydrocarbons (PAHs). In this section, we will discuss the mechanism of vascular endothelial cell damage from two aspects: the main components and their effects.

Extensive evidence indicates that nicotine contributes to vascular endothelial injury through multiple mechanisms, including oxidative stress, inflammatory activation, and regulated cell death.¹¹ Unlike apoptosis, pyroptosis represents a distinct form of inflammatory programmed cell death characterized by inflammasome activation and gasdermin-mediated membrane pore formation.¹⁴ Recent studies have demonstrated that nicotine can promote intracellular reactive oxygen species (ROS) accumulation, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in vascular endothelial cells. Activated NLRP3 facilitates the recruitment and activation of caspase-1, which subsequently cleaves gasdermin D (GSDMD) to generate the pore-forming GSDMD-N fragment. This process results in plasma membrane disruption and the release of mature IL-1β and IL-18, ultimately inducing endothelial pyroptosis and amplifying vascular inflammatory responses during atherosclerotic progression.¹¹ Acrolein exerts cytotoxic effects on human umbilical vein endothelial cells (HUVECs) through three distinct mechanisms. First, it induces an elevation in the intracellular production of ROS, increases the cellular apoptosis rate, and upregulates the expression of 8-hydroxy-2’-deoxyguanosine (8-OHdG)—a widely acknowledged biomarker for oxidative DNA damage. This oxidative stress subsequently activates both p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways. Second, acrolein induces cell cycle arrest at the G0/G1 phase while promoting γ-H2AX (phosphorylated histone H2AX at serine 139) expression and activating the DNA damage response (DDR) pathway. Finally, it triggers apoptosis via upregulation of the Bax/Bcl-2 (Bcl-2-associated X protein/B-cell lymphoma 2) ratio and activation of caspase-3. Tar, which is primarily composed of polycyclic aromatic hydrocarbons, is one of the stable components in smoke,^15,16 polycyclic aromatic hydrocarbons (PAHs) promote endothelial thickening through aryl hydrocarbon receptor (AHR)-mediated induction of inducible nitric oxide synthase (iNOS). Mechanistically, PAH-activated AHR upregulates iNOS expression, which may contribute to pathological vascular remodeling;¹⁷ Benzo[a]pyrene (BaP), a representative PAH present in cigarette smoke, activates the AhR and upregulates leukocyte adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), in human vascular endothelial cells.¹⁸ This amplifies pro-inflammatory signaling at the vascular endothelial surface and promotes monocyte adhesion (Table 1).¹⁹

Table 1.

Mechanism of Cigarette Components Inducing Endothelial Dysfunction

Principal Ingredients	Chemical Structure	Mechanism of Action	Influence
Nicotine		Stimulate ROS production to activate the NLRP3 inflammasome	Pyroptosis,Inflammation
Acrolein		Increased levels of ROS, apoptosis rates, and 8-OHdG, while activating the p38 MAPK and c-Jun N-terminal kinase signaling pathways.	Oxidative stress,Apoptosis
		Induces G0/G1 phase arrest, promotes γ-H2AX expression, activates the DDR signaling pathway.	DNA damage.
		Increased protein expression of Bax/Bcl-2 and caspase-3	Apoptosis
Polycyclic aromatic hydrocarbons		Activation of NADPH oxidase increases the production of O2−	Oxidative stress

Dose-Time Effect

CS and its chemical constituents dose- and time-dependently impair endothelial integrity, thereby contributing to endothelial dysfunction.²⁰ Higher exposure levels or prolonged durations may exacerbate endothelial injury and dysfunction, which may subsequently contribute to atherosclerotic lesion development.²¹

CS exposure dose critically determines the magnitude of vascular endothelial cell damage, exhibiting a clear dose-response relationship in both in vitro and in vivo models.²² Exposure to moderate-to-high doses²³ (eg, >20 cigarettes daily) can cause irreversible damage. Key effects encompass marked DNA damage, impaired mitochondrial function,²⁴ and the degradation of proteins that constitute tight junctions—including zonula occludens-1 (ZO-1) and occludin.²⁵ These changes are accompanied by increased monocyte adhesion and, in severe cases, can trigger pyroptosis¹¹ or apoptosis,²⁰ leading to disruption of the barrier structure.²⁶

Based on duration, CS exposure is categorized as either acute (<48 hours) or chronic. Exposure to acute levels of stress can rapidly induce oxidative stress, suppress antioxidant defenses, and facilitate the release of inflammatory substances. A 24-hour exposure to CSE regulates endothelial cell apoptosis via the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3)/microRNA-421 (miR-421)/DNA fragmentation factor subunit beta (DFFB) signaling axis.²⁷ S. Chen et al demonstrated that a 24-hour treatment of HUVECs with 5% CSE induces ROS accumulation, mitochondrial damage, and activation of autophagy. These events collectively trigger an oxidative stress response.²⁶ Chronic cigarette smoke exposure sustains vascular oxidative stress and endothelial dysfunction. In vascular endothelial cells, cigarette smoke extract induces nuclear and mitochondrial DNA damage²⁴ and promotes apoptosis.²⁸ These alterations may contribute to plaque complications, with direct evidence linking smoke-induced endothelial injury and detachment particularly to superficial plaque erosion.^29,30

In summary, numerous harmful components in CS and CSE are significantly toxic to vascular endothelial cells. This damage exhibits a marked and time-dependent effect. This toxicity provides a mechanistic basis for the development of AS.

Central Mechanistic Themes Linking Endothelial Injury to Plaque Progression

CS disrupts key signaling pathways in vascular endothelial cells, triggering interrelated pathological processes of oxidative stress,¹³ inflammation,³¹ and apoptosis.³² Rather than acting in isolation, these three processes are tightly connected via molecular crosstalk and form a self-amplifying “injury-inflammation-cell death” vicious cycle to exacerbate endothelial injury. This cascade is a core mechanism of endothelial dysfunction. Understanding these mechanisms facilitates the development of novel biomarkers and therapeutic strategies for smoking-related AS.

Oxidative Stress and Nitric Oxide Dysregulation

In cigarette-induced AS, excessive ROS production is a key mechanism contributing to endothelial cell injury and dysfunction.³³

Reactive oxygen species (ROS) are a group of chemically reactive oxygen-containing molecules, including both free radicals, such as the superoxide anion (O₂•⁻) and hydroxyl radical (•OH), and non-radical species, such as hydrogen peroxide (H₂O₂).^34,35 In endothelial cells, nitric oxide (NO) is primarily synthesized by the catalytic activity of endothelial nitric oxide synthase (eNOS). ROS, on the other hand, are mostly produced by enzymes like nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase.^36,37 At physiological concentrations, ROS act as signaling molecules.³⁸ However, when their production exceeds cellular antioxidant defenses—for instance, through eNOS uncoupling—ROS dysregulate NO signaling.³⁹ This promotes the oxidation of lipids and proteins, which impairs mitochondrial function and initiates an oxidative stress cascade. This ultimately leads to endothelial dysfunction.⁴⁰

CS promotes AS by dysregulating NO signaling, which alters hemodynamics, exacerbates oxidative stress, and intensifies inflammation.¹⁰ CS-induced dysregulation of NO signaling involves both impaired eNOS-derived NO bioavailability and aberrant induction of iNOS. eNOS uncoupling reduces NO production and increases superoxide generation, whereas inflammation-associated iNOS induction may lead to excessive NO production, which can further promote nitrosative stress under conditions of elevated superoxide.^41–43 Studies show that CSE triggers oxidative stress in vascular endothelial cells by elevating levels of specific ROS, including superoxide and peroxynitrite. CSE depletes tetrahydrobiopterin (BH4), a crucial cofactor for nitric oxide synthase (NOS). This depletion promotes eNOS uncoupling, reducing eNOS-derived NO production while increasing superoxide generation. The resulting superoxide then reacts with the limited available NO to form peroxynitrite, a more cytotoxic molecule. Peroxynitrite, in turn, oxidizes and depletes additional BH4, creating a vicious cycle that perpetuates eNOS uncoupling and oxidative stress.^10,43 Consequently, the reduction in NO bioavailability impairs endothelium-dependent vasodilation.^44,45 CSE also exerts dose-dependent inhibitory effects on key signaling pathways. It attenuates protein kinase B (Akt) and eNOS phosphorylation at serine residues and inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, and angiogenesis.^45,46 Furthermore, CSE promotes vascular inflammation by inducing the expression of adhesion molecules, which facilitate monocyte adhesion to and infiltration across the endothelial layer.⁹ CSE activates NADPH oxidase, thereby increasing the process of producing ROS. Oxidative stress and endothelial dysfunction, which are caused by these processes, drive the growth of atherosclerotic plaques. This creates a harmful cycle.^29,43

Mounting evidence indicates that oxidative stress may contribute to AS by modifying DNA methylation and histone modifications in endothelial cells through epigenetic pathways. CSE activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway through epigenetic modifications, including enhanced histone H3 lysine 9 (H3K9) acetylation and recruitment of the DNA demethylase ten-eleven translocation methylcytosine dioxygenase 2 (TET2) to the promoters of its target genes (eg, oxidative stress-induced growth inhibitor 1 and 2 (OSGIN1/2))—this enhancement of gene transcription results in increased ROS production within endothelial cells. The elevated ROS inhibits heat shock protein 70 (HSP70) chaperone function, thereby promoting cellular senescence and apoptosis. These findings suggest that epigenetic regulation may contribute to cigarette smoke-induced endothelial dysfunction and may be relevant to atherosclerotic plaque instability.³⁰

In summary, CSE impairs endothelial function by disrupting redox homeostasis through key mechanisms, including eNOS uncoupling, sustained ROS production, and epigenetic regulation (Table 2).

Table 2.

Cigarette Smoke-Induced Oxidative Stress and Associated Molecular Signaling Pathways in Vascular Endothelial Cells

Tobacco-Related Stimulus	Source Of Oxidative Stress	Induced or Dysregulated Signaling Pathway	Endothelial Consequence
CS/CSE	NADPH oxidase activation and mitochondrial dysfunction	Sustained ROS generation and disruption of endothelial redox homeostasis	Oxidative damage, mitochondrial impairment, and endothelial dysfunction
CSE	BH4 depletion and eNOS uncoupling	Reduced eNOS-derived NO, increased superoxide, and peroxynitrite formation	Impaired endothelium-dependent vasodilation and nitrosative stress
CS/CSE-induced oxidative stress	Excessive ROS and redox-sensitive IKK activation	IκBα degradation and NF-κB nuclear translocation	Increased adhesion molecules, cytokines, and endothelial inflammation
CS/CSE-induced oxidative stress	ROS-dependent release and activation of ASK1	ASK1–MKK3/6–p38/MAPK–HSP27 signaling	Cytoskeletal disruption and endothelial apoptosis
Nicotine-induced oxidative stress	Intracellular ROS accumulation	NLRP3–ASC–caspase-1–GSDMD signaling	IL-1β/IL-18 maturation and endothelial pyroptosis

Inflammatory Signaling and Inflammasome Activation

Inflammation is present at all times during AS, from the initial activation of the endothelium to the rupture of the plaque and the subsequent healing process.⁴⁷ As a vital host defense against injury or stimuli, inflammation is primarily regulated by proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). However, upon CS exposure, these very cytokines (eg, TNF-α, IL-6) undergo aberrant induction in vascular endothelial cells, emerging as key drivers of endothelial dysfunction and thus promoting AS progression.^48,49

At the molecular level, CS-induced endothelial inflammation is predominantly mediated by the NF-κB signaling pathway and governed by multilayered, synergistic regulatory mechanisms. Specifically, epigenetic remodeling acts as an upstream regulatory layer to sustain NF-κB-driven pro-inflammatory transcription. The TNF-α/iNOS axis forms a downstream positive feedback loop that further amplifies NF-κB activation. The NLRP3 inflammasome has a dual hierarchical relationship with the NF-κB pathway: The NLRP3 inflammasome is regulated through an initial NF-κB-dependent priming step followed by a second activation step that can be triggered by cellular stress signals, such as ROS, which promotes inflammasome assembly and activation. These two regulatory modes together exacerbate vascular inflammation and endothelial dysfunction.⁵⁰

The NF-κB signaling pathway plays a key role in regulating smoking-induced inflammation in vascular endothelial cells.^51–53 NF-κB is a key pro-inflammatory transcription factor. CS activates NF-κB primarily via ROS generated during oxidative stress. This results in the transcription of a variety of pro-atherogenic genes, including those that encode for adhesion molecules, cytokines, and chemoattractants. The resulting protein products may facilitate inflammatory cell infiltration and create a vascular microenvironment conducive to atherosclerotic lesion development.^54,55 The generation of ROS is the way in which CSE activates the NF-κB pathway, which then initiates a pro-inflammatory response, making it a potent inducer of oxidative stress.⁴⁹ In endothelial cells, ROS can contribute to activation of the IKK–NF-κB pathway, followed by IKK-dependent phosphorylation and degradation of inhibitor of nuclear factor kappa B alpha (IκBα).^56,57 The degradation of IκBα releases NF-κB dimers, including p65/p50, and permits their translocation from the cytoplasm to the nucleus.^54,58 Upon nuclear translocation, NF-κB binds to κB promoter elements, driving the expression of key inflammatory mediators including VCAM-1, intercellular adhesion molecule 1 (ICAM-1), IL-6, and monocyte chemoattractant protein 1 (MCP-1). Together, these mediators promote both monocyte attachment and migration, thereby amplifying the inflammatory response of the endothelium.⁵⁹ In addition to direct redox-sensitive activation of the IKK–NF-κB pathway, receptor-mediated signaling may contribute to cigarette smoke-induced endothelial inflammation. Vascular endothelial cells express pattern-recognition receptors, including Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4). CSE has been reported to increase TLR4 and cyclooxygenase-2 (COX-2) expression in human endothelial cells and to amplify their responses to histamine or LPS, suggesting the potential involvement of a histamine H1 receptor (H1R)–toll-like receptors 2 and 4 (TLR2 and TLR4) inflammatory axis. Canonically, TLR4 recruits myeloid differentiation primary response 88 (MyD88) and activates the interleukin-1 receptor-associated kinase (IRAK)–tumor necrosis factor receptor-associated factor 6 (TRAF6)–transforming growth factor-β-activated kinase 1 (TAK1)–IKK cascade, leading to NF-κB nuclear translocation. NF-κB can also be activated downstream of cytokine receptors; for example, TNF-α activates NF-κB through tumor necrosis factor receptor 1 (TNFR1) in human vascular endothelial cells. However, direct evidence demonstrating that TLR4 is required for CSE-induced NF-κB activation in vascular endothelial cells remains limited.^11,31

As a pro-inflammatory cytokine located downstream of NF-κB, TNF-α amplifies pathological effects through multiple mechanisms.⁶⁰ For instance, TNF-α-induced ROS enhances NF-κB nuclear translocation, which exacerbates the injury to HUVECs. Additionally, TNF-α directly upregulates iNOS and thioredoxin-interacting protein (TXNIP). The subsequent induction of iNOS leads to sustained overproduction of NO, which increases vascular permeability, promotes leukocyte adhesion, and facilitates cytokine release.^61,62 Experimental evidence indicates that iNOS deficiency reverses TNF-α-mediated pathological alterations in HUVECs. Specifically, iNOS loss suppresses the TNF-α-induced upregulation of tumor necrosis factor receptor 2 (TNFR-2), phosphorylated IκBα (p-IκBα), IL-6, VCAM-1, ICAM-1, and cluster of differentiation 31 (CD31). These findings establish iNOS as a key effector molecule regulating downstream inflammatory pathways and vascular endothelial injury in response to TNF-α.⁶³

Epigenetic regulation is increasingly recognized as an important mechanism through which hemodynamic forces shape endothelial phenotype and vascular homeostasis.^64,65 Disturbed blood flow can increase the activity of DNA methyltransferases, including DNA methyltransferase 1 (DNMT1) and DNA methyltransferase 3A (DNMT3A), leading to DNA methylation changes and altered expression of endothelial genes involved in vascular homeostasis.⁶⁶ In addition, shear stress regulates endothelial Krüppel-like factor 2 (KLF2) expression through promoter and chromatin-remodeling mechanisms.⁶⁵ In the context of cigarette smoke exposure, CSE can interact with different shear-stress conditions to alter endothelial inflammatory and antioxidant responses, although the precise epigenetic mechanisms underlying these effects remain to be fully elucidated.⁶⁷

The role of inflammasomes in the acute stress response has attracted considerable attention in the last few years. NLRP3 inflammasome activation generally involves transcriptional priming followed by inflammasome assembly. In human endothelial cells, NF-κB-dependent priming increases the transcription of inflammasome components, including NLRP3, pro-caspase-1, and pro-IL-1β.⁶⁸ Subsequently, nicotine-induced ROS promotes NLRP3–apoptosis-associated speck-like protein containing a CARD (ASC) inflammasome activation in human aortic endothelial cells, resulting in caspase-1 cleavage, IL-1β and IL-18 maturation, and endothelial pyroptosis. ROS scavenging or silencing of NLRP3 or ASC markedly attenuates these effects.¹¹ Research indicates that the NLRP3 inflammasome is activated by nicotine, with this activation subsequently promoting the secretion of extracellular vesicles (EVs). These EVs further promote the upregulation of Toll-like receptors and the expression of inflammation-related factors within the NLRP3 inflammasome. Single-cell RNA sequencing (scRNA-seq) results also show that enhanced protease activity—driven by increased monocyte recruitment and macrophage infiltration—accelerates matrix degradation. This degradation further intensifies the inflammatory response within the vessel lumen, leading to plaque enlargement and reduced stability, which in turn hastens plaque rupture.⁵³

In summary, CS/CSE induces vascular endothelial inflammation through a hierarchically organized regulatory network. Epigenetic remodeling acts as an upstream driver to sustain NF-κB activity; ROS-mediated NF-κB activation serves as the core pathway; the TNF-α/iNOS axis forms a downstream positive-feedback loop to amplify inflammation; and the NLRP3 inflammasome, with both NF-κB-dependent priming and stress-triggered independent activation, synergistically promotes endothelial injury and atherosclerotic progression (Figure 1).

Figure 1.

Cigarette smoke-induced oxidative stress and inflammatory signaling in vascular endothelial cells. (a) CS/CSE induce oxidative stress in vascular endothelial cells: Cigarette smoke (CS), cigarette smoke extract (CSE), and specific tobacco constituents, including nicotine and acrolein, disrupt endothelial redox homeostasis by promoting NADPH oxidase-derived and mitochondrial reactive oxygen species (ROS) production, tetrahydrobiopterin depletion, and endothelial nitric oxide synthase (eNOS) uncoupling. These changes reduce nitric oxide bioavailability and impair endothelial function; (b) CS/CSE induce inflammatory responses in vascular endothelial cells: ROS activates redox-sensitive IKK–NF-κB signaling, whereas receptor-mediated pathways, including TLR2/4- and TNFR-dependent signaling, may further amplify endothelial inflammation. Downstream induction of adhesion molecules and inflammatory cytokines promotes monocyte adhesion and transendothelial migration. Solid arrows indicate mechanisms directly supported by vascular endothelial cell studies; dashed arrows indicate proposed or incompletely established links.

Endothelial Cell Death and Epigenetic Modulation

It is well understood that vascular endothelial cells play a crucial role in maintaining vascular homeostasis. However, CSE disrupts this homeostasis by inducing various forms of programmed cell death, such as pyroptosis, apoptosis, and ferroptosis, in the endothelial cells. This promotes the development of AS.^69,70

Pyroptosis represents a pro-inflammatory type of programmed cell death that relies on inflammasomes. CSE can induce endothelial cell pyroptosis by activating the NLRP3 inflammasome. CSE can either directly activate NLRP3 inflammasomes or promote ROS production by upregulating NADPH oxidase 4 (NOX4), thereby activating NLRP3 inflammasomes.^14,71 This activation further facilitates the assembly of NLRP3 inflammasomes with apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, forming an active complex. The activated caspase-1, on the one hand, cleaves pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) into mature inflammatory cytokines for release. On the other hand, it specifically cleaves Gasdermin D (GSDMD)—a key effector molecule of pyroptosis. The N-terminal domain of GSDMD forms pore-like structures in the cellular membrane, causing rupture and leakage of cellular contents, which ultimately triggers pyroptosis.^11,71–73

Apoptosis is a form of programmed cell death that is generally non-lytic and typically associated with limited inflammatory responses; however, its effects on inflammation may depend on the cellular context and efficiency of apoptotic cell clearance.^74,75 CSE activates the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway via ROS-mediated mitochondrial DNA (mtDNA) release, thereby triggering interferon regulatory factor 3 (IRF3)/NF-κB-dependent inflammation and apoptosis.⁷⁶ ROS can activate stress-responsive MAPK signaling in endothelial cells. In HUVECs, exposure to hydrogen peroxide induces p38 phosphorylation, supporting the responsiveness of endothelial p38 MAPK to oxidative stress.⁷⁷ Acrolein, a reactive aldehyde present in cigarette smoke, increases intracellular ROS and activates p38 MAPK and JNK signaling in HUVECs, accompanied by mitochondrial dysfunction and apoptosis.¹² Acrolein-induced p38 activation also increases COX-2 expression and prostaglandin production, whereas pharmacological inhibition or gene silencing of p38 abolishes these inflammatory responses.⁷⁸ Direct evidence from human aortic endothelial cells further demonstrates that cigarette smoke extract (CSE) activates p38 MAPK and stress-activated protein kinase (SAPK)/JNK, together with caspase-3 and caspase-8 activation and apoptosis; inhibition of either p38 MAPK or JNK attenuates CSE-induced caspase activation.⁷⁹ Sidestream cigarette smoke has also been shown to induce p38 MAPK phosphorylation and increase endothelial permeability, whereas p38 inhibition preserves endothelial barrier integrity.⁸⁰ Collectively, these studies support a mechanistic association between cigarette smoke or its constituent acrolein, oxidative stress, p38/MAPK activation, endothelial inflammation, barrier dysfunction, and apoptosis. This activation accelerates atherosclerotic plaque formation and vascular remodeling.^81–85 Cigarette smoke and its extracts induce significant production of ROS in vascular endothelial cells, causing thioredoxin (Trx) to dissociate from apoptosis signal-regulating kinase 1 (ASK1). This dissociation relieves the inhibitory effect on ASK1, leading to ASK1 phosphorylation. This subsequently triggers the phosphorylation and activation of mitogen-activated protein kinase kinases 3 and 6 (MKK3/6), a key protein in the p38/MAPK signaling pathway, which in turn activates p38.⁸⁰ Activated p38 translocates into the nucleus and phosphorylates heat shock protein 27 (HSP27), which disrupts cytoskeletal stability and ultimately induces apoptosis.^81,82 At the inflammatory response level, pre-incubation with CSE enhances the ability of pro-inflammatory mediators—specifically Endothelial Monocyte-Activating Polypeptide II (EMAP II) and interferon-γ-induced protein 10 kDa (IP-10)—to induce endothelial cell apoptosis. Second, at the epigenetic level, CSE exposure has also been associated with alterations in DNA methylation and histone modifications that may contribute to mitochondrial dysfunction, endothelial apoptosis, and cellular senescence. Previous studies have reported epigenetic changes involving apoptosis- and senescence-related genes in endothelial cells and endothelial progenitor cells following CSE exposure, suggesting that cigarette smoke may modulate endothelial cell fate through epigenetic mechanisms.^28,86–88 However, these findings were obtained from different endothelial cell models and exposure conditions, and the precise contribution of individual epigenetic modifications to cigarette smoke-induced endothelial dysfunction remains to be further clarified.

In addition to apoptosis and pyroptosis, emerging forms of regulated cell death, particularly ferroptosis and cuproptosis, have attracted increasing attention in the context of cigarette smoke-related vascular injury. Ferroptosis is an iron-dependent form of regulated cell death characterized by intracellular iron accumulation and iron-driven lipid peroxidation, and is mechanistically distinct from apoptosis.⁸⁹ Recent evidence provides direct support for a role of ferroptosis in cigarette smoke-related endothelial injury. Fang et al reported that nicotine induces endothelial ferroptosis in the context of atherosclerosis. Mechanistically, nicotine upregulated sequestosome 1 (SQSTM1), which promoted intracellular iron overload and increased reactive oxygen species (ROS) levels, accompanied by elevated levels of the ferroptosis-associated markers heme oxygenase 1 (HMOX1) and prostaglandin-endoperoxide synthase 2 (PTGS2). These alterations were associated with ferroptotic endothelial injury and aberrant production of pro-inflammatory factors. Importantly, pharmacological inhibition of ferroptosis and normalization of intracellular iron levels by SQSTM1 knockdown attenuated endothelial ferroptosis and reduced the production of pro-inflammatory factors, supporting a mechanistic role for ferroptosis in nicotine-induced endothelial dysfunction.⁹⁰ Nevertheless, current mechanistic evidence regarding cigarette smoke-induced ferroptosis in vascular endothelial cells remains relatively limited. Notably, studies in other cigarette smoke-exposed cell types have demonstrated a close association between cigarette smoke exposure and ferroptosis, suggesting that ferroptosis may represent a relatively broad cellular response to tobacco-related stress. These findings provide a rationale for further investigating the potential role of ferroptosis and its underlying molecular mechanisms in cigarette smoke-induced endothelial injury and atherosclerosis.^91–93 Cuproptosis is a recently identified form of regulated cell death that depends on copper ions and was first characterized in 2022.⁹⁴ Its core features include copper-dependent proteotoxic stress and mitochondrial metabolic dysfunction.⁹⁵ Emerging studies have linked cigarette smoke exposure to disruptions in copper homeostasis and cuproptosis-related molecular signatures in pulmonary disease models; however, these findings have primarily been reported in pulmonary epithelial cells or macrophages.⁹⁶ To date, direct experimental evidence demonstrating that cigarette smoke or nicotine can induce cuproptosis in vascular endothelial cells remains lacking. Therefore, cuproptosis may represent a potential emerging mechanism underlying tobacco-related vascular injury, but its specific role in endothelial cells and atherosclerosis remains to be further established.

Importantly, the duration of exposure, the inflammatory and oxidative stress environment, and the cellular availability of specific death effectors may influence the type and extent of endothelial cell death. For example, gasdermin E (GSDME) can link apoptosis and pyroptosis by allowing caspase-3 activation to induce a pyroptotic phenotype in GSDME-expressing cells.^97,98 CSE has also been shown to induce endothelial apoptosis in a dose- and time-dependent manner, supporting the importance of exposure conditions in determining the extent of endothelial injury. However, whether these factors directly determine the choice between apoptosis and pyroptosis in cigarette smoke-exposed endothelial cells remains unclear and requires further investigation.

In summary, multiple signaling pathways act synergistically in cigarette smoke-mediated vascular injury, thereby forming a complex molecular network. Dysregulation of the NF-κB, NO, and MAPK pathways represents an important molecular basis of CS-induced endothelial dysfunction and may contribute to the development and progression of AS. A comprehensive understanding of the interactions among these signaling pathways may provide a theoretical basis for developing targeted intervention strategies for smoking-related AS in the future (Figure 2).

Figure 2.

Regulated endothelial cell death induced by cigarette smoke and its constituents. (a) Nicotine-induced ROS activates the NLRP3–ASC–caspase-1–GSDMD pathway, leading to inflammatory cytokine maturation and endothelial pyroptosis; (b) CS, CSE, and acrolein promote endothelial apoptosis through oxidative stress-associated pathways involving mitochondrial injury, cGAS–STING signaling, and ASK1–p38/MAPK activation; (c) Nicotine-induced SQSTM1 upregulation, iron accumulation, and lipid peroxidation have been implicated in vascular endothelial ferroptosis. Evidence for ferroptosis induced by whole cigarette smoke remains limited and is partly derived from non-endothelial models; these indirect or proposed mechanisms are indicated by dashed arrows. Collectively, these forms of cell death disrupt endothelial barrier integrity and promote vascular inflammation.

Mechanistic Crosstalk

Cigarette smoke-induced endothelial injury is not mediated by oxidative stress, inflammation, and cell death as independent events; rather, accumulating evidence indicates that these processes are closely interconnected and contribute to the amplification of endothelial injury.^99,100 Cigarette smoke exposure increases ROS generation in vascular endothelial cells, partly through activation of NADPH oxidases and disruption of endothelial redox homeostasis. Excessive ROS can subsequently activate redox-sensitive NF-κB signaling, leading to increased expression of pro-inflammatory cytokines and adhesion molecules, including TNF-α, IL-1β, IL-6, ICAM-1, VCAM-1, and E-selectin.¹⁰¹

The inflammatory response, in turn, can further aggravate endothelial injury and promote cell death. In cigarette smoke extract-treated human pulmonary artery endothelial cells, increased TNF-α signaling is associated with activation of Tumor necrosis factor receptor 1 (TNFR1), NF-κB signaling, inflammatory responses, and endothelial apoptosis; pharmacological inhibition of TNF-α/TNFR1 signaling attenuates CSE-induced inflammatory and apoptotic responses.¹⁰² In addition, cigarette smoke exposure has been shown to induce endothelial apoptosis through mitochondrial and caspase-dependent mechanisms, supporting the close relationship between persistent smoke-induced cellular stress and endothelial cell death.²⁸

Oxidative stress can also connect cigarette smoke exposure to inflammatory forms of regulated cell death. In endothelial cells exposed to CSE, ROS accumulation promotes NLRP3 inflammasome activation, accompanied by increased ASC, cleaved caspase-1, GSDMD-N, IL-1β, and IL-18. Importantly, both ROS scavenging and pharmacological inhibition of NLRP3 attenuate CSE-induced endothelial pyroptosis, providing direct evidence for a ROS–NLRP3–caspase-1–GSDMD axis linking oxidative stress to inflammatory cell death.¹⁰³

Taken together, oxidative stress, inflammation, and endothelial cell death form an interconnected and mutually reinforcing network in cigarette smoke-induced endothelial injury, rather than acting as isolated events. Their reciprocal amplification sustains endothelial dysfunction and may contribute to atherosclerotic progression.^104,105

From Endothelial Injury to Atherosclerotic Plaque Progression

Mechanistic Links to Plaque Development and Complications

Extensive experimental studies have confirmed the close link between cigarette smoke exposure, endothelial injury, and atherosclerotic plaque development.¹⁰⁴ Long-term CS exposure can induce vascular endothelial cell injury and apoptosis,²⁰ elevate blood lipid levels, including total cholesterol and triglycerides,¹⁰⁶ promote excessive release of inflammatory mediators, and increase the subendothelial accumulation of oxidized low-density lipoprotein (ox-LDL), thereby disrupting endothelial barrier integrity.¹⁰⁷ These pathological changes promote monocyte adhesion and transendothelial migration.⁵⁹ After being recruited into the intima, monocytes differentiate into macrophages, take up modified lipoproteins through scavenger receptors such as lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and subsequently develop into foam cells. Endothelial apoptosis further compromises the continuity of the endothelial monolayer, perpetuates barrier dysfunction, and ultimately promotes plaque formation and destabilization.¹⁰⁸

Consistent with these processes, environmental tobacco smoke exposure has been shown to increase carotid arterial permeability and LDL accumulation in rats,^107,109 whereas cigarette smoke condensate increases endothelial adhesion molecule expression and promotes monocyte transendothelial migration.⁵⁹ Collectively, these findings support mechanistic links between smoke-induced endothelial injury and early atherogenic events, including arterial LDL accumulation and monocyte recruitment, which contribute to the initiation and subsequent progression of atherosclerotic plaques. The signaling mechanisms described below provide a molecular basis for the development of atherosclerotic plaques following endothelial injury. Nicotine suppresses endothelial GTP cyclohydrolase 1 (GTPCH1), thereby reducing tetrahydrobiopterin (BH4) availability and nitric oxide (NO) production while increasing reactive oxygen species (ROS) generation. The resulting disruption of endothelial redox homeostasis impairs vascular function. In apolipoprotein E-deficient (ApoE⁻/⁻) mice, GTPCH1 overexpression or BH4 supplementation improves endothelial function and attenuates nicotine-accelerated atherosclerosis.¹¹⁰ Meanwhile, nicotine-stimulated monocytes release miR-155-containing extracellular vesicles, which transfer miR-155 to endothelial cells and promote NF-κB activation, inflammatory responses, monocyte adhesion, and endothelial apoptosis. Administration of these extracellular vesicles aggravates endothelial injury and plaque formation in ApoE⁻/⁻ mice, whereas inhibition of microRNA-155 (miR-155) attenuates these effects.⁵³ Thus, impaired NO signaling and enhanced inflammatory signaling translate molecular alterations into endothelial dysfunction, leukocyte recruitment, and endothelial cell loss, thereby linking endothelial signaling changes directly to atherosclerotic lesion formation.

Endothelial responses to tobacco constituents may also influence vascular smooth muscle cell behavior and thereby contribute to plaque remodeling. Conditioned medium from nicotine-treated endothelial cells promotes vascular smooth muscle cell migration, supporting paracrine communication between nicotine-exposed endothelium and neighboring smooth muscle cells.¹¹¹ After their recruitment into atherosclerotic lesions, smooth muscle cells undergo phenotypic modulation that influences plaque composition. Krüppel-like factor 4 (KLF4)-dependent modulation can promote lesion growth and plaque characteristics associated with reduced stability, whereas transcription factor 21 (TCF21)-dependent transition into fibromyocytes contributes to the formation of a protective fibrous cap.^112,113 Together, these findings suggest that nicotine-induced endothelial signals promote smooth muscle cell migration, while subsequent smooth muscle cell phenotypic modulation influences lesion expansion and fibrous cap formation. Direct evidence linking tobacco-induced endothelial signaling to necrotic core formation remains limited. Although smoke-induced endothelial barrier dysfunction and leukocyte recruitment may create a lipid-rich and pro-inflammatory environment that favors subsequent macrophage death and necrotic core expansion, this downstream process has not been directly demonstrated in tobacco-exposed endothelial models. Tobacco-associated endothelial mechanisms may also contribute differently to plaque rupture and erosion. Cigarette smoke induces matrix metalloproteinase-1 (MMP-1) expression in rabbit aortic endothelium, while cigarette smoke extract and acrolein increase MMP-1 and decrease tissue inhibitor of metalloproteinases-3 (TIMP-3) in cultured aortic endothelial cells, suggesting a potential endothelial contribution to extracellular matrix degradation; however, a direct endothelial-cell-specific causal link to fibrous cap rupture has not been established.¹¹⁴ More direct evidence exists for plaque erosion: in human coronary artery endothelial cells exposed to cigarette smoke extract and TNF-α under elevated shear stress, activation of the Nrf2–OSGIN1/2 pathway causes loss of focal adhesions, disturbed proteostasis, and endothelial detachment, whereas OSGIN1/2 knockdown attenuates this effect.³⁰

Collectively, these findings indicate that tobacco-induced endothelial dysfunction connects molecular signaling alterations with lipid retention, leukocyte recruitment, vascular cell communication, and endothelial loss, thereby contributing to plaque initiation, progression, and erosion, although its direct roles in necrotic core formation and plaque rupture remain to be established.

Hemodynamic Dysfunction and Loss of Endothelial Homeostasis

Endothelial impairment and hemodynamic imbalance is recognized as the initial events and key pathological mechanisms in the onset and progression of AS lesions.^115,116 Substantial evidence indicates that CS synergistically impairs vascular function through multiple pathways, disrupting blood flow stability and thereby creating a microenvironment conducive to AS lesion development.²⁴

CS induces excessive ROS production, disrupting NO synthesis and bioavailability in endothelial cells. This leads to impaired vasodilation, reduced vascular compliance, and elevated systolic blood pressure.³³ As a key mediator for maintaining vascular relaxation and anti-inflammatory effects, NO dysfunction can significantly impair the stress regulatory capacity of blood vessels, promote the development of hypertension, and thereby create a favorable environment for AS lesions. However, multiple animal studies have shown that following CS exposure, mice develop vascular endothelial cell damage, accompanied by reduced NO levels and increased O₂•⁻ levels. Additionally, manifestations include elevated blood pressure, insufficient local arterial perfusion, arrhythmia, and fluctuations in arterial blood flow.^29,117

In summary, CS disrupts the homeostasis of vascular endothelial function and hemodynamics through multiple mechanisms. This persistent dysregulation of vascular homeostasis not only exacerbates arterial inflammatory responses and lipid deposition but also provides a critical pathological basis for the development and progression of AS lesions.⁹

Vascular Remodeling, Inflammatory Infiltration, and Plaque Instability

In addition to the aforementioned mechanisms, a growing body of evidence suggests that CS can induce vascular remodeling and inflammatory infiltration. These steps are also crucial for the development and progression of AS lesions.

Research data using ApoE⁻/⁻ animal models consistently demonstrate that animals exposed to mainstream tobacco smoke exhibit reduced aortic elasticity,¹¹⁸ impaired diastolic function,¹¹⁹ thickened aortic walls,¹²⁰ endothelial dysfunction,¹¹⁸ elevated circulating inflammatory markers,¹²¹ impaired vasodilation and coagulation regulation.¹²² Regarding cigarette smoke-induced inflammatory infiltration, Sawa et al demonstrated that administering IQOS aerosol—similar to cigarette smoke—to mice elevated plasma IL-6 levels, thereby increasing the risk of AS.¹²³ Secondly, CS increases levels of markers of oxidative stress, such as pro-inflammatory cytokines (interleukin-2 (IL-2), interleukin-8 (IL-8), and TNF-α), as well as high-sensitivity C-reactive protein. This triggers inflammatory responses and vascular endothelial cell dysfunction, which contribute to the progression of AS.⁴⁹

In summary, CS-induced vascular structural remodeling and inflammatory infiltration not only disrupt the normal architecture and function of blood vessels but also promote the onset and development of cardiovascular disease (Figure 3).

Figure 3.

From cigarette smoke-induced endothelial injury to atherosclerotic plaque progression and potential therapeutic intervention. CS, CSE, and specific tobacco constituents induce endothelial oxidative stress, inflammation, barrier disruption, and cell death. The resulting increase in endothelial permeability, lipid retention, adhesion molecule expression, and monocyte recruitment contributes to plaque initiation and progression. Subsequent smooth muscle cell migration and phenotypic modulation, macrophage foam-cell formation, defective efferocytosis, necrotic-core expansion, and extracellular matrix remodeling occur primarily in non-endothelial vascular cells and influence fibrous-cap stability. Loss or detachment of endothelial cells may contribute directly to superficial plaque erosion, whereas the link between smoke-induced endothelial injury and plaque rupture is mainly indirect and requires further investigation. Established clinical treatments are distinguished from preclinical or proposed endothelial-targeted interventions.

Latest Clinical Treatment Strategies and Future Prospects

CS is a major causative factor in AS lesions, underscoring the importance of identifying effective interventions. Current therapeutic strategies for smoking-related atherosclerotic disease vary considerably in their levels of evidence and clinical applicability. Therefore, these interventions can be broadly considered in four categories: established clinical therapies, nutraceuticals or natural compounds, preclinical interventions, and exploratory drug-delivery strategies.

First, established clinical therapies have relatively strong clinical evidence and constitute the foundation of current management for atherosclerotic cardiovascular disease.¹²⁴ Smoking cessation is a cornerstone of cardiovascular risk reduction in individuals who smoke and is essential for preventing continued tobacco-related vascular injury.^125,126 In addition, current management includes lipid-lowering therapy, antiplatelet therapy, blood pressure control, diabetes management, and revascularization where appropriate.¹²⁴ Among these approaches, statins remain an important component of lipid-lowering therapy and exert anti-inflammatory, lipid-lowering, plaque-stabilizing, and potentially endothelial-protective effects by inhibiting endoplasmic reticulum stress, enhancing eNOS activity, and downregulating the NF-κB pathway.^{52,53,118,127}

A second category includes nutraceuticals and natural bioactive compounds.¹²⁸ In this context, antioxidants—including vitamins C and E, mitochondria-targeted ubiquinone (MitoQ), and polyphenolic compounds—are recognized as adjunctive therapies. Studies have demonstrated that these agents can improve endothelial function, alleviate damage induced by oxidative stress, and inhibit the development of atherosclerotic lesions.^26,129 However, the clinical efficacy of these antioxidants remains controversial, potentially due to individual differences and suboptimal dosage selection.¹³⁰

Although current therapeutic strategies can reduce overall cardiovascular risk and partially improve lipid abnormalities and oxidative stress,^124,131 their primary effects are not specifically directed toward the complex molecular network underlying cigarette smoke-induced vascular endothelial injury.^131,132 Moreover, although statins are generally well tolerated, long-term use may cause adverse reactions such as abnormal liver function, new-onset diabetes, and myopathy.¹³³ In addition, the efficacy of statins in reversing smoking-induced oxidative stress and endothelial damage is limited, indicating the need for additional therapeutic strategies to improve treatment outcomes. Persistent oxidative stress can further activate inflammatory signaling and regulated cell death and interact with these processes to form a self-amplifying pathological cycle. Therefore, conventional risk-factor management and general antioxidant interventions alone may be insufficient to fully address smoking-induced endothelial injury, highlighting the need to further identify actionable molecular nodes within this pathogenic network. On this basis, this review focuses on the Wnt/β-catenin pathway, the TXNIP/NLRP3 axis, and the p38 MAPK pathway as potential therapeutic targets for further discussion. These pathways were not selected to provide an exhaustive overview of all emerging therapeutic directions, but rather because they are directly connected to the major pathological mechanisms described above: Wnt/β-catenin signaling is closely associated with endothelial dysfunction and vascular remodeling;¹³⁴ the TXNIP/NLRP3 axis links oxidative stress to inflammasome activation and pyroptosis; and p38 MAPK is involved in smoke-related cellular stress, endothelial barrier dysfunction, and apoptosis.^79,80 Further investigation of these pathways may therefore provide a natural extension from the mechanistic framework established above to potential targeted therapeutic strategies. The precise mechanisms by which CS influences the proliferation, migration, and apoptosis of vascular endothelial cells via the Wnt signaling pathway remain poorly understood. Specifically, CS may promote vascular remodeling and atherosclerotic plaque formation by activating the Wnt/β-catenin pathway. Molecular targets—including Wnt ligands (eg, Wnt5a), Frizzled receptors, β-catenin, and p66Shc—show promise as potential therapeutic intervention points.¹³⁵ Recent studies have revealed that the thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome pathway also plays a crucial role in macrophage pyroptosis. Inhibiting this pathway may mitigate tobacco smoke-induced vascular endothelial damage.¹³⁶ As indicated in Endothelial Cell Death and Epigenetic Modulation of this paper, targeting the p38α mitogen-activated protein kinase (p38α MAPK) subtype or its upstream kinases (eg, apoptosis signal-regulating kinase 1 [ASK1]) is also considered a promising therapeutic avenue.^78–80,137

With the revival of traditional Chinese medicine, herbal therapies for atherosclerosis have gained increasing attention. However, resveratrol—an antioxidant—can inhibit CS-induced p38 MAPK phosphorylation, thereby suppressing the activation of the MAPK pathway.⁸⁰ Additionally, rhodiola glycosides^138,139 alleviate atherosclerotic lesions by inhibiting apoptosis in vascular endothelial cells and mitigating associated inflammatory responses. The active tanshinone components inhibit the Wnt3a/p66Shc/ROS axis, thereby mitigating the vascular endothelial impairment and DNA damage caused by tobacco smoke. Additionally, these components upregulate the anti-apoptotic protein Bcl-2 and suppress the pro-apoptotic protein Bax. They also inhibit CSE-induced vascular endothelial cell apoptosis and block the NF-κB pathway, thereby counteracting inflammation.^135,140,141

Finally, novel drug-delivery technologies, such as nanodelivery systems, have been developed to improve the stability, bioavailability, and tissue targeting of candidate therapeutic compounds.¹⁴² For example, an OX26-modified polyethylene glycol-conjugated cationic solid lipid nanoparticle (OX26-PEG-CSLN) particle, a cationic lipophilic solid lipid nanodelivery particle modified with polyethylene glycol and loaded with baicalin, has been developed.¹⁴³ Building on this approach, future studies may further explore the incorporation of specific active traditional Chinese medicine (TCM) compounds, such as tanshinones, into nanocarriers for targeted delivery to sites of vascular endothelial injury, thereby providing a potential therapeutic strategy for cigarette smoke-induced vascular injury.

Although therapeutic approaches for atherosclerotic disease associated with smoking continue to advance, existing treatment strategies still confront considerable challenges regarding therapeutic effectiveness, disease prognosis, long-term safety profiles, and ethical aspects.

Conclusion and Perspectives

In summary, exposure to CS and CSE can cause significant vascular endothelial injury through multiple cellular and molecular pathways, thereby contributing to the development and progression of AS. Endothelial dysfunction represents a key pathological consequence of this injury and an important mechanism linking smoking exposure to atherosclerotic development. This process involves the triggering of several important cellular signaling pathways, including those of NF-κB, NO synthesis, MAPK, Wnt, and the NLRP3 inflammasome. These activations lead to the cascading amplification of oxidative stress, inflammatory responses, and apoptotic imbalance.

Funding Statement

This work was supported by the National Natural Science Foundation of China (No. 32260156) and the Key Projects of the Foundation of Guizhou Science and Technology Cooperation (No. ZK2022-050).

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

Xin Sheng: Conceptualization, Validation, Writing – review and editing, Supervision, Project administration, and Funding acquisition. Xiangjun Chen: Conceptualization, Methodology, Software, Investigation, Data curation, Project administration, Visualization, Writing – original draft, and Writing – review and editing. Xinran Yang: Conceptualization, Investigation, Data curation, Writing – original draft, and Writing – review and editing. Zhihan Li: Conceptualization, Investigation, Data curation, Writing – original draft, and Writing – review and editing. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest.