Cell‐Type–Specific Regulation of Ferroptosis in Atherosclerosis: Mechanisms and Therapeutic Potential of Natural Products

ABSTRACT

Ferroptosis is a regulated form of cell death in which disturbed iron metabolism, accumulation of peroxidized membrane lipids, and insufficient glutathione peroxidase 4 (GPX4) activity converge to injure vascular cells. In atherosclerosis, its effects are highly dependent on cellular context rather than being uniform across the vessel wall. In macrophages, ferroptotic injury strengthens inflammatory signaling and contributes to necrotic‐core growth; in vascular smooth muscle cells, it impairs mitochondrial fitness, contractile phenotype maintenance, and extracellular matrix support, thereby weakening the fibrous cap; and in endothelial cells, it disrupts redox homeostasis and barrier function, facilitating lipid entry and early lesion formation. This review synthesizes recent advances in the molecular regulation of ferroptosis in atherosclerosis and emphasizes how its functional consequences differ among plaque‐resident cell types. We also discuss natural products and traditional Chinese medicine‐derived compounds as promising modulators of ferroptosis‐related pathways, owing to their multi‐target actions and potential suitability for chronic vascular intervention. By connecting mechanistic evidence with therapeutic implications, we propose that cell‐type‐aware regulation of ferroptosis, rather than indiscriminate suppression, may offer a rational strategy for plaque stabilization and cardiovascular risk reduction.

Significance:

• Ferroptosis is increasingly recognized as an important contributor to atherosclerosis, but its vascular effects vary substantially among endothelial cells, macrophages, and vascular smooth muscle cells.

• This review analyzes how cell‐specific differences in iron handling, lipid peroxidation, and antioxidant defenses shape plaque initiation, inflammatory progression, and fibrous‐cap stability.

• We further summarize evidence that natural compounds can modulate these ferroptosis‐related networks and restore redox and cellular homeostasis.

• By linking vascular cell heterogeneity with natural product‐based intervention strategies, this review provides a mechanistic and translational framework for more precise targeting of ferroptosis in atherosclerosis.

Summary

• Ferroptosis produces cell‐type‐specific effects across atherosclerotic plaques.

• Macrophage ferroptosis amplifies inflammation and necrotic‐core expansion.

• VSMC ferroptosis weakens fibrous‐cap integrity and promotes plaque instability.

• Endothelial ferroptosis disrupts barrier function and facilitates lipid entry.

• Natural products offer multi‐target, cell‐aware strategies for plaque stabilization.

1. Introduction

Programmed cell death (PCD), including apoptosis, necroptosis, pyroptosis, autophagy, PANoptosis and ferroptosis, contributes to tissue homeostasis by removing damaged or unnecessary cells [1, 2]. This intricate mechanism not only contributes to normal development and tissue remodeling but also plays a pivotal role in the pathogenesis of numerous diseases [3]. Atherosclerosis (AS) is a progressive inflammatory disease characterized by lipid accumulation, endothelial injury, and activation of immune responses [4]. Among the PCD pathways implicated in AS, ferroptosis has attracted particular interest since its description by Dixon et al. in 2012 as an iron‐dependent death program associated with lipid peroxide accumulation [5]. Ferroptosis differs from classical PCD both morphologically and biochemically [6]. Ferroptotic cells typically display shrunken mitochondria with increased membrane density and reduced cristae, while nuclear morphology is relatively preserved [7]. Biochemically, ferroptosis is characterized by iron overload [8], glutathione depletion, and the inactivation of glutathione peroxidase 4 (GPX4), resulting in the accumulation of lethal lipid reactive oxygen species (ROS) [9].

Excessive iron accumulation and lipid peroxidation have been observed within atherosclerotic plaques [10], especially in macrophages, vascular smooth muscle cells (VSMCs), and endothelial cells (ECs)—key mediators of plaque formation and instability [11]. In these cells, iron‐driven ROS production can promote endothelial activation, foam‐cell formation, inflammatory amplification, and plaque vulnerability [12]. In VSMCs, Ferrostatin‐1 (Fer‐1) reduces iron accumulation by regulating transferrin receptor 1 (TFR1), ferritin heavy chain (FTH1), and ferritin light chain (FTL) [13]. In ECs, oxidized low‐density lipoprotein (ox‐LDL) induces ROS generation and GPX4 downregulation, impairing endothelial integrity, whereas ferroptosis inhibition restores barrier function [14]. In macrophages, excess iron enhances ROS generation and favors pro‐inflammatory M1 polarization, linking iron overload to ferroptosis‐associated inflammatory activation [15]. Consistently, hepcidin knockout in LDLR‐deficient mice decreases macrophage iron levels and reduces M1 macrophage accumulation within plaques [16]. Ferroptosis inhibitors, including deferoxamine (DFO) [17], ferrostatin‐1 (Fer‐1) [18], and liproxstatin‐1 (Lip‐1) [19] have also been reported to reduce plaque area or improve vascular function in experimental AS models.

Although these studies have advanced the mechanistic understanding of ferroptosis in AS, much of the existing work relies on genetic manipulation or synthetic ferroptosis inhibitors. Comparatively fewer studies have examined therapeutic approaches that are practical for long‐term regulation in chronic vascular disease. Because AS is multifactorial and ferroptosis plays distinct roles in macrophages, VSMCs, and ECs, interventions that simultaneously influence redox stress, iron handling, lipid metabolism, and inflammatory signaling may be especially useful. Natural products and traditional Chinese medicine‐derived compounds therefore represent an underexplored source of ferroptosis modulators [20]. Their pleiotropic biological activities and generally favorable suitability for chronic disease management make them attractive candidates for sustained and multi‐target vascular protection. Emerging evidence indicates that such compounds can modulate ferroptosis in a cell‐dependent manner and thereby affect plaque initiation, progression, and stability.

Taken together, current findings suggest that ferroptosis in plaque‐resident cells is closely linked to AS progression. Accordingly, this review summarizes the molecular regulation of ferroptosis, emphasizes cell‐specific functions in macrophages, VSMCs, and ECs, and evaluates natural products as potential modulators of ferroptosis for AS prevention and treatment (Table 1).

Table 1.

Distinct morphological, biochemical, and genetic characteristics of major PCD modalities.

Type	Morphological hallmarks	Biochemical features	Representative genes/regulators	References
Ferroptosis	Shrunken mitochondria; reduced or vanished cristae; condensed membrane densities.	Iron overload and lipid peroxidation; suppression of GPX4 activity; inhibition of the System Xc− antiporter; depletion of GSH; accumulation of lipid ROS.	TFRC, SLC7A11, FSP1, GPX4, NCOA4, ACSL4, ALOXs, Nrf2	[1]
Apoptosis	Cell shrinkage and rounding; chromatin condensation; nuclear fragmentation; membrane blebbing; apoptotic body release.	Activation of caspase cascade; externalization of phosphatidylserine; internucleosomal DNA cleavage.	CASP3, CASP8, FAS, BCL2, BAX, TP53	[1]
Necroptosis	Cell and organelle swelling; plasma membrane rupture; moderate chromatin condensation.	Loss of ATP; activation of RIPK1, RIPK3, and MLKL leading to necrosome formation.	RIPK1, RIPK3, MLKL, LEF1	[1]
Pyroptosis	Cellular swelling and membrane pore formation; bubble‐like protrusions; intact nuclear morphology.	Assembly of inflammasome complexes; cleavage of GSDMs by inflammatory caspases; secretion of IL‐1β and IL‐18.	NLRP3, CASP1, CASP4/5/11, GSDMD, IL‐1β, IL‐18	[1]
Autophagy	Accumulation of double‐membrane autophagosomes; increased lysosomal activity.	Elevated autophagic flux; activation of autophagy‐related signaling cascades.	LC3, ATG5, ATG7, BECN1, DRAM3, TFEB	[1]
PANoptosis	Hybrid morphology combining features of apoptosis, pyroptosis, and necroptosis.	Formation of PANoptosome complexes integrating caspase and RIPK signaling.	ZBP1, RIPK1, RIPK3, FADD, CASP1, CASP8	[2]

2. Molecular Mechanisms of Ferroptosis

2.1. Free Iron Accumulation

Iron is an essential trace metal element that plays critical roles in oxygen transport, mitochondrial respiration, DNA synthesis, and numerous enzymatic reactions [21]. In healthy tissues, systemic and intracellular iron fluxes are tightly coordinated to support these functions while preventing toxic accumulation. When this balance is disrupted, expansion of redox‐active ferrous iron (Fe²⁺) can initiate iron‐dependent oxidative injury and promote ferroptotic signaling [22].

Iron enters the cell primarily in two transport forms: transferrin‐bound iron (TBI) and non‐transferrin‐bound iron (NTBI) [23]. In the TBI pathway, circulating ferric iron (Fe³⁺) bound to transferrin interacts with TFR1 and is internalized by receptor‐mediated endocytosis. Endosomal acidification releases Fe³⁺ [24], which is reduced by STEAP3 and transported into the cytosol through DMT1. In iron‐overloaded states, the iron‐binding capacity of transferrin becomes saturated, leading to the appearance of NTBI, which represents labile Fe²⁺ or Fe³⁺ species bound to small ligands such as citrate or ATP [25]. NTBI can be directly taken up by cells through alternative pathways, including ZIP14, also known as solute carrier protein family 39 member 14 (SLC39A14) or calcium channels, bypassing the normal regulatory checkpoints of TBI. Notably, NTBI uptake is especially active in pathological conditions such as hemochromatosis, inflammation, and AS [26].

Within the cytoplasm, redox‐active iron contributes to the labile iron pool (LIP). Although this pool supports biosynthetic and metabolic reactions, excess Fe²⁺ catalyzes the Fenton reaction, converting hydrogen peroxide (H₂O₂) into hydroxyl radicals (•OH). These radicals initiate lipid peroxidation and oxidative stress, which are central biochemical features of ferroptosis [27].

Cells limit iron toxicity by controlling iron storage and export. Ferritin, composed of FTH1 and FTL subunits, stores excess iron in a less reactive Fe³⁺ form [28]. During stress or autophagy activation, ferritin can be delivered to lysosomes through NCOA4‐mediated ferritinophagy, releasing stored iron back into the LIP and thereby increasing ferroptosis susceptibility [29]. Iron export is mediated by ferroportin (FPN1, encoded by SLC40A1), the only known cellular iron exporter [30]. Hepcidin negatively regulates FPN1 by promoting its internalization and degradation; dysregulation of this hepcidin‐FPN1 axis, especially in plaque macrophages, favors iron retention, lipid peroxidation, and inflammation [31].

Thus, ferroptosis‐related iron accumulation reflects the combined effects of increased iron import through TFR1 or NTBI routes, ferritin degradation through NCOA4‐dependent ferritinophagy, and reduced iron efflux through hepcidin‐FPN1 signaling. These events expand the intracellular Fe²⁺ pool, disturb redox balance, and drive the lipid damage that characterizes ferroptotic cell death.

2.2. Lipid Peroxidation

Lipid peroxidation represents the execution phase of ferroptosis because it compromises membrane integrity and ultimately leads to cell death. The process involves oxidative damage to polyunsaturated fatty acids (PUFAs), particularly those incorporated into membrane phospholipids, and culminates in the formation of lipid hydroperoxides (LOOHs) [32]. Both non‐enzymatic and enzymatic reactions contribute to this process, and both are influenced by intracellular redox‐active iron [33]. In non‐enzymatic reactions, Fe²⁺‐driven Fenton chemistry generates •OH that abstract bis‐allylic hydrogens from PUFAs such as arachidonic acid (AA) and adrenic acid (AdA). The resulting lipid radicals (L•) react with oxygen to form lipid peroxyl radicals (LOO•), propagate radical chain reactions, and generate toxic LOOHs [34]. These modifications are particularly severe when occurring on polyunsaturated fatty acids, such as AA or AdA, esterified to phosphatidylethanolamine (PE), which are particularly vulnerable within the cell membrane [35]. Accumulation of oxidized PE species, including PE‐AA‐OOH, destabilizes membrane structure, increases permeability, and triggers ferroptosis [36]. These species can also act as pro‐inflammatory and immunogenic mediators, contributing to secondary damage in tissue contexts such as AS [37].

Enzymatic lipid oxidation also contributes substantially to ferroptotic injury. Members of the lipoxygenase (LOX) family oxygenate PUFAs and thereby promote lipid peroxide formation. Among them, arachidonate 15‐lipoxygenase (ALOX15) has been widely investigated because it catalyzes the site‐specific oxidation of AA‐ or AdA‐containing PE species, producing lipid hydroperoxides that can directly execute ferroptosis [38]. These enzymatically generated peroxides constitute a distinct oxidative product pool that cannot be fully explained by non‐enzymatic radical chemistry alone [39].

The availability of oxidizable substrates depends on lipid remodeling. Free PUFAs are first ligated to coenzyme A by acyl‐CoA synthetase long‐chain family member 4 (ACSL4), generating PUFA‐CoA intermediates. Lysophosphatidylcholine acyltransferase 3 (LPCAT3) then incorporates these activated fatty acids into membrane phospholipids, enriching membranes with PE species that are susceptible to oxidation [40]. Inhibition of ACSL4 or LPCAT3, either genetically or pharmacologically, reduces PUFA‐PE formation and confers resistance to ferroptosis, underscoring the importance of lipid remodeling in the execution phase of this death program [41].

2.3. Amino Acid Metabolism

Disruption of amino acid metabolism, particularly cystine (Cys)–glutamate (Glu) exchange via system Xc⁻, represents a third critical mechanism in ferroptosis regulation [4]. system Xc⁻ is a sodium‐independent antiporter composed of two subunits: Solute Carrier Family 7 Member 11 (SLC7A11), the specific light‐chain transporter responsible for substrate recognition, and solute carrier family 3 member 2 (SLC3A2), a heavy‐chain subunit that functions as a chaperone [42]. This transporter imports extracellular Cys into the cell in exchange for intracellular Glu, where Cys is rapidly reduced to cysteine, a rate‐limiting precursor for Glutathione (GSH) synthesis [43]. GSH is an essential intracellular antioxidant that serves as a cofactor for GPX4, the central enzyme responsible for detoxifying lipid hydroperoxides and suppressing ferroptosis [44]. Pharmacological inhibition of System Xc⁻ by erastin or genetic suppression of SLC7A11 decreases Cys uptake, depletes cysteine and GSH pools, and weakens GPX4 activity [45]. This GSH deficiency impairs GPX4 enzymatic activity, thereby preventing the reduction of LOOHs to non‐toxic lipid alcohols. As a result, LOOHs are no longer efficiently reduced to non‐toxic lipid alcohols, allowing membrane lipid peroxides to accumulate and trigger ferroptotic death [46].

SLC7A11 expression is controlled by stress‐responsive transcriptional programs. Nuclear factor erythroid 2‐related factor 2 (Nrf2) and activating transcription factor 4 (ATF4) can enhance SLC7A11 transcription during oxidative or endoplasmic reticulum stress [47], whereas tumor protein p53 may repress SLC7A11 and sensitize cells to ferroptosis in selected contexts [48]. In addition, excess intracellular Glu generated by sustained exchange or glutaminolysis can aggravate excitotoxic and redox stress [49]. The GSH/GPX4 axis also depends on cysteine supplied through alternative routes, including the transsulfuration pathway, which converts methionine‐derived intermediates into cysteine [50]. During System Xc⁻ inhibition, this compensatory pathway may partially restore cysteine availability, although it is often insufficient to fully prevent ferroptosis without exogenous Cys [51].

Overall, disruption of System Xc⁻ limits cysteine supply, reduces GSH biosynthesis, impairs GPX4‐dependent lipid peroxide detoxification, and promotes ferroptosis. Because this pathway integrates amino acid transport with redox homeostasis, System Xc⁻ and its upstream regulators are important molecular nodes for controlling ferroptosis in vascular and other disease contexts (Figure 1).

Figure 1.

Regulatory pathways of ferroptosis. Ferroptosis is a regulated cell death modality characterized by iron‐dependent accumulation of lipid peroxides. (1) Ferroptosis is a regulated form of cell death driven by iron‐dependent lipid peroxidation. Intracellular Fe²⁺ accumulates through multiple pathways, including Tf‐mediated uptake via TFR1, NTBI transporters (ZIP14/DMT1), and ferritin degradation (ferritinophagy) mediated by NCOA4. Excess intracellular Fe²⁺ participates in the Fenton reaction, producing •OH that catalyze lipid peroxidation. (2) PUFAs are esterified into membrane phospholipids by the coordinated actions of ACSL4 and LPCAT3, forming PUFA‐PLs. LOXs, particularly ALOX15, catalyze the enzymatic oxygenation of these phospholipids, yielding PUFA‐OOH. Accumulation of lipid ROS leads to membrane damage and ferroptosis. (3) Amino acid metabolism & antioxidant defense: TheSystem Xc⁻ supplies cystine for GSH biosynthesis. GPX4 catalyzes the reduction of PUFA‐OOH to PUFA‐OH, using GSH as the reducing cofactor. Inhibition of System Xc⁻ or GPX4 collapses redox defense, allowing lipid ROS to accumulate and execute ferroptosis. Copyright statement: This figure was created by the authors and contains no previously published images.

2.4. Other Antioxidant Pathways

Iron loading, lipid peroxidation, and amino acid metabolism constitute the core metabolic framework of ferroptosis. However, additional antioxidant and lipid‐defense systems can modulate ferroptosis sensitivity independently of the classical GSH‐GPX4 pathway. Several GPX4‐independent mechanisms and lipid remodeling programs act in parallel with canonical defenses, enabling cells to buffer oxidative lipid stress and shape ferroptosis outcomes when primary metabolic defenses are compromised [52] (Figure 2).

Figure 2.

GPX4‐independent pathways. In addition to the canonical GPX4/GSH pathway, several parallel antioxidant pathways suppress ferroptosis by preventing lipid peroxidation. (1) FSP1/CoQ10/NAD(P)H pathway: FSP1 reduces CoQ10 to ubiquinol CoQ10H₂ using NAD(P)H as an electron donor. Ubiquinol and α‐TOH act as radical‐trapping antioxidants, terminating lipid peroxidation chains at the plasma membrane. (2) GCH1/BH4/DHFR pathway: GCH1 synthesizes BH4 from GTP. BH4, regenerated from BH2 by DHFR, directly scavenges lipid radicals and supports α‐tocopherol recycling, thereby inhibiting lipid peroxidation. (3) DHODH/CoQ10 pathway: Within mitochondria, DHODH reduces CoQ10 to CoQ10H₂, limiting mitochondrial PLOOH accumulation and restraining mtROS‐driven ferroptosis. Together, these GPX4‐independent systems provide complementary defense mechanisms that maintain redox homeostasis and prevent ferroptosis. Copyright statement: This figure was created by the authors and contains no previously published images.

2.4.1. Ferroptosis Inhibitory Protein 1 (FSP1)/CoQ10/NAD(P)H Pathway

FSP1‐CoQ10‐NAD(P)H pathway has gained increasing attention as a robust, GPX4‐independent system that suppresses ferroptosis through a distinct mechanism of lipid radical scavenging [53]. FSP1, also known as AIFM2 (Apoptosis‐inducing factor mitochondria‐associated 2), is a flavoprotein that has been identified as a potent ferroptosis suppressor. FSP1 functions by reducing CoQ10 (ubiquinone) to its antioxidant form, CoQ10H2 (ubiquinol), using NAD(P)H as an electron donor [54]. As a lipophilic radical‐trapping antioxidant, CoQ10H2 acts either by directly reducing lipid radicals or by indirectly maintaining antioxidant capacity through the recycling of α‐tocopherol (α‐TOH) [55].

Because this pathway does not depend on GSH, it can protect cells when GPX4 function is impaired, such as during GSH depletion or pharmacological GPX4 inhibition by RSL3 [56]. Genetic depletion or functional inhibition of FSP1 increases ferroptosis sensitivity in experimental models, confirming its role as a compensatory lipid‐antioxidant system [57]. Together with the GSH‐GPX4 axis, the FSP1‐CoQ10‐NAD(P)H pathway forms a parallel defense network and may represent a therapeutic target in ferroptosis‐related diseases.

2.4.2. Gtp Cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4)/dihydrofolate Reductase (DHFR) Pathway

The GCH1/BH4/DHFR pathway constitutes a GPX4‐independent mechanism that protects against ferroptosis by limiting lipid peroxidation [58]. GCH1 is the rate‐limiting enzyme in the de novo biosynthesis of BH4, a pteridine cofactor traditionally known for its roles in nitric oxide synthesis and aromatic amino acid hydroxylation [59]. Recent studies have shown that BH4 functions as a potent lipophilic antioxidant by scavenging lipid peroxyl radicals, stabilizing PUFA‐containing membrane phospholipids, and enhancing CoQ10 levels to support redox homeostasis [60]. The antioxidant capacity of BH4 depends not only on its synthesis via GCH1, but also on its regeneration from its oxidized form, dihydrobiopterin (BH2), through the activity of DHFR [61]. This recycling ensures a sustained pool of reduced BH4 capable of continuous ROS neutralization. Disruption of either GCH1 or DHFR expression sensitizes cells to ferroptosis by impairing BH4‐mediated lipid protection [62]. In addition, a genome‐wide CRISPR screening study identified GCH1 as a ferroptosis‐suppressor gene, and functional analyses demonstrated that GCH1 overexpression enhances BH4 biosynthesis and confers resistance to ferroptosis in mouse fibroblasts treated with RSL3 [63].

This pathway appears to be context dependent and may be particularly relevant in cell types with PUFA‐rich membranes, such as endothelial cells and neurons [64]. Anti‐ferroptotic activity of the GCH1/BH4 axis has also been described in tumors, where BH4 accumulation protects against PUFA membrane oxidation and suppresses ferroptosis under oxidative stress [65]. Because it functions independently of GSH and GPX4, the GCH1/BH4/DHFR axis may provide an alternative protective mechanism when canonical antioxidant systems are weakened.

2.4.3. Dihydroorotate Dehydrogenase (DHODH)/CoQ10 Pathway

The DHODH/CoQ10 pathway plays a crucial role in ferroptosis by regulating mitochondrial function and oxidative stress [66]. DHODH is located in the inner mitochondrial membrane, where it oxidizes dihydroorotate to orotate during pyrimidine biosynthesis and transfers electrons to CoQ10. This reaction generates reduced CoQ10H2, which scavenges lipid peroxyl radicals and limits mitochondrial lipid peroxidation and membrane injury [67]. DHODH cooperates with GPX4 to restrain mitochondrial ferroptosis; when GPX4 is impaired, DHODH activity can become particularly important for maintaining CoQ10H2 production and reducing lipid peroxide accumulation [68].

Pharmacological inhibition of DHODH, for example by leflunomide, or genetic suppression of DHODH reduces mitochondrial CoQ10‐dependent protection and increases ferroptosis sensitivity by promoting lipid peroxidation and mitochondrial dysfunction [69]. Conversely, CoQ10 supplementation can alleviate ferroptotic injury under oxidative stress, supporting the importance of this pathway for mitochondrial integrity and cellular redox balance.

3. Ferroptosis‐Driven Functional Disruption Across Vascular Cell Types in AS

3.1. Ferroptosis‐Driven Macrophage Dysfunction Promotes Necrotic Core Expansion and Inflammation

Macrophages contribute to AS by controlling foam‐cell formation, inflammatory signaling, and clearance of dying cells within plaques. Ferroptosis in macrophages should therefore be viewed not only as a terminal death process but also as a driver of functional imbalance that accelerates lesion progression. When macrophages accumulate Fe²⁺, undergo lipid peroxidation, and lose GPX4 activity, they release inflammatory mediators and promote lesion enlargement and instability [70]. Evidence from pharmacological and natural product‐based interventions further indicates that limiting macrophage ferroptosis can help restore macrophage homeostasis and attenuate AS progression [71].

A hallmark feature linking macrophage ferroptosis to plaque vulnerability is dysregulated iron handling within the atherosclerotic microenvironment. In regions of intraplaque hemorrhage, macrophages exposed to erythrophagocytosis accumulate excessive heme‐derived iron, leading to intracellular iron retention and heightened susceptibility to ferroptosis. This iron‐driven cell death impairs effective clearance of dying cells and promotes secondary necrosis, thereby directly contributing to necrotic core expansion [72]. Ferroptosis inhibition in such plaques reduces macrophage death and local inflammation, supporting iron metabolism as a central determinant of macrophage fate in advanced lesions. Mechanistically, hepcidin‐ferroportin imbalance, NCOA4‐mediated ferritinophagy, and cathepsin B (CTSB)‐dependent ferroportin degradation collectively reinforce a pro‐ferroptotic iron milieu [73, 74].

Failure of antioxidant defenses provides a second mechanism by which macrophages acquire a ferroptosis‐prone and pro‐inflammatory phenotype [75]. The atherogenic stimulus ox‐LDL suppresses the Nrf2/SLC7A11/GPX4 axis and disturbs redox homeostasis, thereby promoting macrophage ferroptosis [76]. Reduced GPX4 activity facilitates lipid peroxide accumulation and also affects macrophage lipid handling by enhancing uptake of modified lipoproteins and impairing cholesterol efflux, favoring foam‐cell formation [77]. Conversely, restoration of Nrf2/GPX4 signaling preserves redox balance and macrophage function. For example, interleukin 37 (IL‐37) promotes Nrf2 nuclear translocation and increases GPX4 expression, thereby mitigating ferroptosis under pro‐atherogenic conditions [78].

The susceptibility of macrophages to ferroptosis is further amplified by the hostile plaque microenvironment. Hypoxic conditions commonly observed in advanced lesions activate hypoxia‐inducible factor‐1α and heme oxygenase‐1, promoting lipid peroxidation and sensitizing foam cells to ferroptotic death [79, 80]. Exogenous stressors such as cigarette tar can amplify this process by inducing iron overload and oxidative stress through NF‐kappaB‐dependent inflammatory signaling and disruption of iron export machinery [81]. These observations illustrate how local and environmental insults jointly enhance ferroptotic injury in plaque macrophages.

At a regulatory level, emerging evidence suggests that epigenetic and post‐transcriptional mechanisms fine‐tune macrophage susceptibility to ferroptosis rather than acting as primary drivers. Non‐coding RNAs, m6A RNA methylation mediated by methyltransferase‐like 3 (METTL3), and histone lactylation collectively modulate the expression and stability of key ferroptosis‐related genes, including SLC7A11 and GPX4 [82, 83]. These regulatory layers function to stabilize a ferroptosis‐prone transcriptional and metabolic state in macrophages under chronic inflammatory and metabolic stress, thereby reinforcing functional impairment once ferroptosis is initiated.

Several synthetic and metabolic interventions have provided proof‐of‐concept evidence that macrophage ferroptosis is a druggable process. Pharmacological ferroptosis inhibitors [84], metabolic modulators [85], and autophagy‐related pathways [86] have been shown to reduce iron accumulation, lipid peroxidation, and inflammatory activation in macrophages, thereby attenuating atherosclerotic lesion development in experimental models.

A growing body of evidence indicates that natural products and traditional Chinese medicine (TCM)‐derived formulations modulate macrophage ferroptosis through several convergent mechanisms rather than through isolated compound‐specific effects. In macrophages, the pathological consequence of ferroptosis is closely linked to iron retention, lipid accumulation, inflammatory amplification, and defective plaque clearance. Therefore, natural product–based interventions should be interpreted according to their ability to restore macrophage functional homeostasis, rather than simply according to whether they reduce ferroptosis markers.

One major mechanistic theme is the restoration of antioxidant defense through the SIRT1/Nrf2/GPX4 and Nrf2/SLC7A11/GPX4 axes. Several natural monomers converge on this pathway to counteract ox‐LDL‐induced oxidative stress and lipid peroxidation in macrophages. Paeonol (PAE) and paclitaxel (PTX) both suppress macrophage ferroptosis through SIRT1‐dependent activation of Nrf2 and GPX4, thereby reducing foam cell lipid accumulation and attenuating atherosclerotic lesion development [87, 88]. Similarly, tricetin restores Nrf2 signaling and upregulates GPX4 and SLC7A11, suggesting that reinforcement of the cystine–GSH–GPX4 antioxidant system represents a central mechanism by which natural compounds preserve macrophage viability and redox balance under atherogenic stress [89]. Rather than representing separate pharmacological observations, these studies collectively identify the SIRT1/Nrf2/GPX4‐centered antioxidant module as a recurring protective axis in macrophage ferroptosis.

A second theme involves stabilization of the Keap1–Nrf2 regulatory interface, which links redox sensing to ferroptosis resistance. Panax notoginseng saponins (PNS), Micheliolide (MCL), and Oleuropein (OL) all ultimately enhance Nrf2‐dependent antioxidant responses, although through distinct upstream mechanisms. PNS sustains Nrf2 activation by suppressing USP2‐mediated Keap1 deubiquitination, whereas MCL and OL interfere directly with Keap1–Nrf2 interactions, thereby promoting Nrf2 nuclear translocation and antioxidant gene expression [90, 91, 92]. These findings suggest that natural products may suppress macrophage ferroptosis not merely by scavenging reactive oxygen species, but by recalibrating the endogenous redox‐sensing machinery that determines macrophage susceptibility to lipid peroxidation.

A third mechanism is the coordinated regulation of ferroptosis, inflammation, and lipid‐handling functions. This feature is particularly important in macrophages because ferroptotic injury is tightly coupled to foam cell formation, cytokine release, and necrotic core expansion. TCM formulations such as Qing‐Xin‐Jie‐Yu Granule (QXJYG) and Huotan Jiedu Tongluo Decoction (HTJDTLD) exemplify this multi‐level regulation. QXJYG stabilizes plaques by activating the GPX4/xCT antioxidant system, whereas HTJDTLD suppresses macrophage ferroptosis through the Nrf2/autophagy axis, accompanied by reduced reactive oxygen species production, improved lipid metabolism, and attenuation of atherosclerotic lesion progression [93, 94]. These formulation‐based interventions support the concept that ferroptosis modulation in macrophages is therapeutically meaningful only when it is accompanied by improvement in inflammatory and lipid‐processing functions.

Finally, targeted delivery strategies further extend the mechanistic potential of natural product–based macrophage ferroptosis modulation. Macrophage‐specific nanodrug systems co‐loading pitavastatin and resveratrol suppress foam cell ferroptosis by reprogramming metabolic and stress‐response pathways, whereas antibody‐modified nanocarriers delivering polyamines restore mitochondrial function and enhance GPX4/xCT activity [95, 96]. These approaches address a key translational limitation of natural compounds—limited specificity—and suggest that macrophage‐targeted delivery may maximize anti‐ferroptotic efficacy while reducing systemic off‐target effects.

Collectively, natural products counteract macrophage ferroptosis through interconnected antioxidant, iron‐handling, inflammatory, metabolic, and delivery‐related mechanisms. Their therapeutic value lies not simply in preventing macrophage death, but in restoring macrophage functional balance, limiting foam cell dysfunction, reducing inflammatory amplification, and restraining necrotic core expansion. This mechanism‐based interpretation provides a more integrated framework for understanding natural product–mediated plaque stabilization (Table 2).

Table 2.

Natural products targeting macrophage ferroptosis in As.

Natural product/formulation	Source	Key ferroptosis‐related mechanisms	Major effects in AS	References
PAE	Paeonia lactiflora Pallas	Activates SIRT1/Nrf2/GPX4 axis; restores antioxidant defense and iron homeostasis	Reduces foam cell lipid accumulation; suppresses macrophage ferroptosis; attenuates lesion development	[87]
PTX	Pacific yew	SIRT1‐dependent activation of Nrf2 and GPX4; effect abolished by SIRT1 inhibition	Alleviates macrophage ferroptosis; improves plaque stability	[88]
Tricetin	Wheat	Activates Nrf2, upregulates GPX4 and SLC7A11	Suppresses oxidative stress and ferroptosis; slows atherosclerotic progression	[89]
PNS	Panax notoginseng	Inhibits USP2‐mediated Keap1 deubiquitination; sustains Nrf2 signaling	Reduces macrophage ferroptosis and inflammation	[90]
MCL	Active metabolite of parthenolide	Directly interferes with Keap1–Nrf2 interaction	Promotes antioxidant gene expression; inhibits ferroptosis	[91]
OL	Olive leaves	Binds Keap1 arginine residues; enhances Nrf2 nuclear translocation	Suppresses macrophage ferroptosis; alleviates AS progression	[92]
QXJYG	Traditional Chinese medicine formula	Activates GPX4/xCT antioxidant system	Inhibits macrophage ferroptosis; enhances plaque stability[	[93]
HTJDTLD	Traditional Chinese medicine formula	Activates Nrf2/autophagy axis; reduces ROS	Suppresses ferroptosis; improves lipid metabolism and delays AS	[94]
Pitavastatin + Resveratrol nanodrug	Natural product–based nanotherapy	Reprograms stress‐response pathways; inhibits ferroptosis	Reduces lipid accumulation and inflammation within plaques	[95]
Polyamine‐loaded nanocarriers	Natural polyamines	Restores mitochondrial function; enhances GPX4/xCT activity	Effectively suppresses macrophage ferroptosis	[96]

3.2. VSMC Ferroptosis Compromises Fibrous Cap Integrity and Plaque Stability

VSMCs are major components of the arterial media and fibrous cap and are essential for plaque structure and stability during AS [97]. In their contractile state, VSMCs regulate vascular tone and produce extracellular matrix (ECM) [98]. In the atherosclerotic microenvironment, however, oxidized lipoproteins, mechanical stress, and chronic inflammation drive phenotypic switching, mitochondrial dysfunction, and regulated cell death [99]. Growing evidence suggests that VSMC ferroptosis is not simply an end‐stage death event; it disrupts functional homeostasis, weakens fibrous‐cap architecture, and increases plaque vulnerability [100].

Ox‐LDL can induce VSMC ferroptosis, as reflected by Fe²⁺ accumulation, lipid peroxidation, and reduced GPX4 activity. These changes impair redox balance and contractile capacity, thereby undermining ECM maintenance required for fibrous‐cap stability [101]. Heat shock protein beta‐1 (HSPB1) counteracts ox‐LDL‐induced ferroptosis by inhibiting NF‐kappaB‐dependent upregulation of dipeptidyl peptidase 4 (DPP4). Pharmacological DPP4 inhibition similarly reduces ferroptosis markers and restores GPX4 expression, highlighting a protective pathway that preserves VSMC integrity under atherogenic stress [101].

Antioxidant failure also sensitizes VSMCs to ferroptosis. Nrf2 activation increases SLC7A11 and GPX4 expression, strengthens glutathione‐dependent redox buffering, and limits lipid peroxide accumulation. For example, catechin activates Nrf2/SLC7A11/GPX4 signaling and suppresses ox‐LDL‐induced ferroptotic stress in VSMCs [102].

Metabolic reprogramming further influences VSMC ferroptosis. The Yes‐associated protein 1 (YAP1)‐glutaminase 1 (GLS1) axis supports glutamate and glutathione biosynthesis, thereby sustaining antioxidant capacity and ferroptosis resistance. Loss of YAP1 increases ferroptosis sensitivity, whereas YAP1 activation restores redox balance and preserves VSMC viability and contractile potential. These data indicate that VSMC ferroptosis is closely tied to metabolic fitness and phenotype maintenance rather than to inflammatory activation alone [103].

Animal studies further show that ferroptosis modulation affects VSMC fate and plaque stability. In ApoE‐/‐ mice, ferroptosis inhibitors reduce lesion size, relieve iron overload, and restore antioxidant proteins such as Nrf2, FSP1, ferritin light chain, and ferritin heavy chain. These effects may occur independently of the canonical xCT/GPX4 pathway, suggesting that alternative ferroptosis‐regulatory circuits also help preserve VSMCs and fibrous‐cap integrity [104].

Additional regulatory pathways add complexity to VSMC ferroptosis. Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibition induces VSMC ferroptosis by suppressing GPX4 and ferritin and by activating autophagy‐dependent iron mobilization. Although MALT1 inhibition can attenuate AS progression in experimental models, excessive VSMC ferroptosis may impair vascular contractility, underscoring the context‐dependent nature of ferroptosis in vascular remodeling [105]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) exacerbates VSMC ferroptosis by promoting lysosomal degradation of YAP1 and weakening antioxidant and metabolic resilience, suggesting that PCSK9‐targeted strategies may stabilize plaques not only through lipid lowering but also by preserving VSMC function [106].

VSMC ferroptosis is also linked to chronic structural remodeling. In advanced plaques, ferroptotic injury can contribute to vascular calcification and fibrous‐cap weakening. Oleoylethanolamide (OEA) attenuates ferroptosis‐associated calcification by enhancing mitochondrial function and suppressing ferritinophagy through coordinated activation of peroxisome proliferator‐activated receptor alpha (PPARα) and inhibition of the cyclic GMP‐AMP synthase (cGAS), and stimulator of interferon genes (STING1) signaling pathway, further linking ferroptosis regulation to long‐term structural remodeling of the vessel wall [107].

Natural products targeting VSMC ferroptosis can be more clearly synthesized according to the functional requirements of VSMCs within atherosclerotic plaques. Unlike macrophages, where ferroptosis mainly amplifies inflammation and necrotic core formation, VSMC ferroptosis directly compromises contractile phenotype maintenance, mitochondrial metabolism, extracellular matrix homeostasis, and fibrous cap stability. Therefore, the therapeutic relevance of natural compounds in VSMCs should be evaluated by whether they preserve structural and mechanical plaque integrity, rather than by ferroptosis inhibition alone.

The first major mechanism is reinforcement of antioxidant defense and glutathione‐dependent lipid peroxide detoxification. Catechin, a dietary flavonoid abundant in green tea, attenuates ox‐LDL‐induced VSMC ferroptosis by activating the Nrf2/SLC7A11/GPX4 axis, thereby reducing ferrous iron accumulation, lipid peroxidation, and mitochondrial damage [102]. Echinatin, a chalcone derived from Glycyrrhiza inflata, acts through a related but distinct redox mechanism by upregulating the glutamate–cysteine ligase subunits GCLC and GCLM, thereby sustaining glutathione biosynthesis and limiting ferroptotic lipid injury [108]. These findings indicate that maintenance of the glutathione–GPX4 antioxidant network is a central protective module for preserving VSMC viability and function under atherogenic stress.

A second theme is the regulation of mitochondrial iron homeostasis and ferritinophagy. This mechanism is particularly relevant to VSMCs because mitochondrial dysfunction can impair contractile capacity and promote phenotypic switching. The Gualou–Xiebai (GLXB) herb pair suppresses VSMC ferroptosis by inhibiting LOX‐1–dependent NCOA4 activation and reducing NCOA4–FTMT‐associated mitochondrial iron dysregulation [109]. Through limiting mitochondrial iron overload, mitoROS generation, and mitochondrial membrane potential collapse, GLXB links ferritinophagy control to preservation of VSMC metabolic stability. This suggests that targeting mitochondrial iron handling may be especially important for maintaining fibrous cap integrity in advanced plaques.

A third mechanism involves preservation of VSMC phenotype and extracellular matrix stability through redox‐sensitive signaling networks. Huangqi Chifeng Decoction (HQCF) activates the thioredoxin (TXN)/xCT/GPX4 axis, improves antioxidant capacity, maintains mitochondrial integrity, and suppresses VSMC ferroptosis and foam cell formation [110]. Importantly, this effect is not limited to cell survival; it is also associated with stabilization of the contractile phenotype, which is essential for collagen production and fibrous cap maintenance. Together with the effects of echinatin on VSMC–ECM interactions, these findings suggest that natural products may protect plaques by coupling ferroptosis suppression with preservation of the biomechanical functions of VSMCs.

Thus, natural product–mediated regulation of VSMC ferroptosis can be summarized into three interconnected modules: antioxidant and glutathione restoration, mitochondrial iron/ferritinophagy control, and preservation of contractile–matrix homeostasis. This synthesis highlights that VSMC‐directed ferroptosis modulation should not be interpreted as simple cytoprotection. Instead, its major pathological significance lies in maintaining fibrous cap stability, preventing excessive vascular remodeling, and reducing plaque vulnerability (Table 3).

Table 3.

Natural products targeting VSMC ferroptosis in As.

Natural product/formulation	Source	Key ferroptosis‐related mechanisms	Major effects in AS	References
Catechin	Green tea polyphenol	Activates Nrf2/SLC7A11/GPX4 axis; reduces iron accumulation, lipid peroxidation, and mitochondrial damage	Suppresses VSMC ferroptosis; limits foam cell formation; preserves mitochondrial ultrastructure and plaque stability	[102]
Echinatin	Glycyrrhiza inflata (chalcone)	Upregulates GCLC/GCLM, sustains glutathione biosynthesis; inhibits lipid peroxidation and ferroptosis	Attenuates VSMC ferroptosis; preserves VSMC–ECM interactions; mitigates arterial stiffening and AS	[108]
GLXB	Traditional Chinese medicine herb pair	Inhibits LOX‐1–NCOA4–FTMT axis; suppresses ferritinophagy‐mediated mitochondrial iron overload	Reduces mitoROS and ferroptosis; restrains VSMC proliferation and migration; preserves mitochondrial function	[109]
HQCF	Traditional Chinese medicine formula	Activates TXN–xCT–GPX4 axis; improves antioxidant capacity and mitochondrial integrity	Suppresses VSMC ferroptosis and foam cell formation; stabilizes contractile phenotype and fibrous cap	[110]

3.3. ECs Ferroptosis Initiates Vascular Dysfunction and Accelerates Atherogenesis

ECs, which line the luminal surface of blood vessels, play a fundamental role in maintaining vascular barrier integrity, sensing hemodynamic forces, and regulating lipid permeability and inflammatory cell recruitment [111]. Endothelial dysfunction represents one of the earliest and most critical events in AS initiation [112]. Ferroptosis contributes to this dysfunction not merely by causing cell loss but by disturbing barrier function, redox balance, and vascular homeostasis during early atherogenesis [113].

Ox‐LDL induces ferroptotic stress in ECs, accompanied by iron accumulation, lipid peroxide formation, and suppression of GPX4. These changes impair redox balance and mitochondrial function, weaken membrane integrity, and increase endothelial permeability, facilitating lipid entry into the subendothelial space [114, 115, 116]. Oxidized phospholipids enriched in atherosclerotic lesions, including 1‐palmitoyl‐2‐glutaroyl‐sn‐glycero‐3‐phosphocholine (PGPC), further aggravate endothelial ferroptosis through CD36‐dependent lipid uptake and fatty acid‐binding protein‐mediated lipid peroxidation [117].

Endothelial ferroptosis is tightly regulated by intracellular antioxidant and iron‐handling systems, among which the Nrf2/SLC7A11/GPX4 axis represents a central protective mechanism. Activation of Nrf2 enhances cystine uptake, glutathione biosynthesis, and GPX4 activity, thereby limiting lipid peroxidation and preserving endothelial viability [118]. Disruption of this pathway increases EC ferroptosis and accelerates endothelial dysfunction. Multiple metabolic and stress‐responsive regulators converge on this redox defense network, underscoring the importance of antioxidant homeostasis for endothelial integrity under atherogenic stress [109, 119].

Disordered iron metabolism further amplifies endothelial ferroptotic injury. Ferritin degradation, limited iron export, and ferritinophagy‐mediated iron release expand the labile iron pool and promote lipid peroxidation and mitochondrial damage [120]. Environmental and lifestyle‐related exposures, including cigarette smoke components, pollutants, and ionizing radiation, can worsen these events by increasing iron accumulation, ROS generation, and antioxidant failure, thereby linking real‐world stressors to endothelial ferroptosis and accelerated AS progression [121, 122, 123, 124, 125].

Post‐transcriptional and epigenetic regulation also shapes endothelial ferroptosis by altering genes involved in iron handling and antioxidant defense. These regulatory layers appear to reinforce a ferroptosis‐prone state during chronic metabolic and inflammatory stress rather than acting as independent initiators, contributing to persistent endothelial dysfunction [126, 127, 128, 129].

Collectively, endothelial ferroptosis promotes early atherogenesis by weakening barrier integrity, increasing lipid permeability, and amplifying inflammatory signaling. Iron loading, oxidative stress, and insufficient antioxidant defense converge to render ECs vulnerable to ferroptotic injury. Restoring endothelial redox balance and iron homeostasis may therefore help preserve endothelial function and interrupt early plaque development.

Natural products that protect ECs from ferroptosis can be organized into recurring modules centered on barrier preservation. Because endothelial ferroptosis contributes to early atherogenesis by disturbing redox balance, increasing permeability, and facilitating lipid infiltration, the therapeutic question is not only whether a compound lowers ferroptosis markers but whether it maintains endothelial integrity. A first mechanism is direct suppression of oxidative stress, lipid peroxidation, and iron accumulation. Isopropyl 3‐(3,4‐dihydroxyphenyl)−2‐hydroxypropionate (IDHP) attenuates palmitic acid‐induced endothelial ferroptosis by reducing ROS production, lipid peroxidation, and iron accumulation [130]. Icariin similarly alleviates endothelial ferroptotic injury in high‐fat diet‐induced AS models by suppressing oxidative stress and lipid peroxidation while promoting adaptive autophagy [131]. These findings suggest that early endothelial protection requires simultaneous control of redox imbalance and iron‐dependent membrane damage.

The second and most recurrent theme is activation of Nrf2‐centered antioxidant defense. Several structurally diverse natural products converge on this pathway through different upstream regulators. Hydroxysafflor Yellow A (HSYA) modulates the miR‐429/SLC7A11 axis, upregulates GPX4 and xCT, and suppresses ACSL4, thereby limiting lipid peroxide accumulation [132]. Quercetin (QCT) activates the Nrf2/GPX4 pathway through KEAP1 ubiquitination, whereas ecdysterone activates PI3K/Akt/Nrf2 signaling and inhibits NCF2‐dependent oxidative injury [133, 134]. Tanshinone IIA (TSA) and 6‐gingerol further reinforce this antioxidant module by promoting Nrf2 activation and upregulating downstream antioxidant enzymes such as HO‐1 and NQO1 [135, 136]. Collectively, these studies indicate that the Nrf2‐related redox network represents a central convergence point for natural product–mediated protection against endothelial ferroptosis.

A third mechanism involves inhibition of lipid peroxidation machinery and restoration of ferroptosis‐related protein homeostasis. Berberine (BBR) suppresses ACSL4‐driven lipid peroxidation and restores ferroptosis‐related protein balance, thereby limiting endothelial injury and plaque formation [137]. PAE protects endothelial cells by regulating HMOX1 and PI3K/Akt signaling, reducing iron overload, suppressing lipid peroxidation, and restoring endothelial viability [138]. These findings highlight that endothelial ferroptosis can be controlled not only by strengthening antioxidant defenses, but also by restraining the upstream lipid remodeling and iron‐dependent processes that generate lethal lipid peroxides.

A fourth theme is the integration of ferroptosis regulation with autophagy, mitochondrial function, and systemic metabolic signals. Matrine reduces iron‐dependent lipid peroxidation and preserves endothelial integrity through activation of the PI3K/Akt/mTOR pathway via regenerating family member 1 alpha [139]. Capsiate activates the Nrf2/GPX4 axis and reduces plaque burden, while also modulating gut microbiota composition, suggesting that endothelial ferroptosis may be influenced by systemic metabolic and inflammatory environments [140]. These observations broaden the interpretation of natural products from direct endothelial antioxidants to multi‐level regulators of vascular homeostasis.

Finally, TCM formulations illustrate the advantage of multi‐target regulation in endothelial ferroptosis. GLXB simultaneously reduces oxidative stress, limits iron‐dependent lipid peroxidation, preserves mitochondrial integrity, and restores endothelial redox balance by activating Nrf2‐dependent defenses and suppressing LOX‐1/cGAS–STING/NCOA4‐mediated ferritinophagy [141]. Tongxinluo (TXL) and QiXian Granule (QXG) similarly protect endothelial cells by stabilizing GPX4 and ferritin function, preserving barrier integrity, and reducing iron‐dependent oxidative damage [142, 143]. These formulation‐based effects support the idea that endothelial ferroptosis is best targeted through combined regulation of antioxidant capacity, iron storage, mitochondrial protection, and barrier maintenance.

Overall, natural products protect ECs from ferroptosis through four major modules: suppression of oxidative lipid damage, activation of Nrf2/GPX4‐related antioxidant defenses, inhibition of lipid peroxidation and iron‐overload pathways, and preservation of mitochondrial and barrier function. By maintaining endothelial integrity, these interventions may reduce lipid infiltration and inflammatory recruitment during the earliest stages of atherogenesis (Table 4).

Table 4.

Natural products targeting ECs ferroptosis in As.

Natural product/formulation	Source	Key ferroptosis‐related mechanisms	Major effects in AS	References
IDHP	Natural phenolic derivative	Reduces ROS generation, lipid peroxidation, and intracellular iron accumulation	Attenuates endothelial ferroptosis; delays vascular aging–associated endothelial dysfunction	[130]
Icariin	Epimedium species	Suppresses ROS and lipid peroxidation; promotes autophagy‐mediated adaptation	Alleviates endothelial ferroptosis; preserves endothelial function	[131]
HSYA	Carthamus tinctorius	Regulates miR‐429/SLC7A11 axis; upregulates GPX4 and xCT; inhibits ACSL4	Reinforces antioxidant defense; protects endothelial integrity	[132]
QCT	Dietary flavonoid	KEAP1 ubiquitination–mediated activation of Nrf2/GPX4	Suppresses endothelial ferroptosis; reduces lipid peroxidation and iron accumulation	[133]
Ecdysterone	Natural plant sterol	Activates PI3K/Akt/Nrf2 pathway; inhibits NCF2	Mitigates ferroptotic injury; reduces oxidative stress and inflammation	[134]
BBR	Coptis chinensis	Inhibits ACSL4‐driven lipid peroxidation	Restores ferroptosis‐related protein homeostasis; limits endothelial injury and plaque formation	[135]
PAE	Paeonia lactiflora Pallas	Regulates HMOX1 and PI3K/Akt signaling; reduces iron overload	Inhibits lipid peroxidation; restores endothelial viability	[136]
TSA	Salvia miltiorrhiza	Activates Nrf2 signaling; restores antioxidant capacity	Suppresses canonical ferroptosis; reduces ROS accumulation	[137]
6‐Gingerol	Ginger (Zingiber officinale)	Promotes Nrf2 nuclear translocation; upregulates HO‐1 and NQO1	Dampens oxidative injury, inflammation, and ferroptosis	[138]
Matrine	Sophora flavescens	Activates PI3K/Akt/mTOR via REG1A	Reduces iron‐dependent lipid peroxidation; preserves endothelial integrity	[139]
Capsiate	Sweet pepper derivative	Activates Nrf2/GPX4 axis; modulates gut microbiota	Suppresses endothelial ferroptosis; reduces plaque burden	[140]
GLXB	Traditional Chinese medicine herb pair	Activates Nrf2; inhibits LOX‐1/cGAS–STING/NCOA4–ferritinophagy	Limits iron release and ferroptotic injury; preserves mitochondrial and redox homeostasis	[141]
TXL	Traditional Chinese medicine formula	Stabilizes GPX4 and ferritin function	Improves endothelial barrier integrity; reduces iron‐dependent oxidative damage	[142]
QXG	Traditional Chinese medicine formula	Maintains GPX4 and ferritin activity; reduces iron overload	Preserves endothelial integrity; attenuates AS progression	[143]

4. Discussion

AS is a multifactorial chronic vascular disease in which dysregulated cell death contributes not only to lesion growth but also to plaque instability and clinical complications. In this review, we synthesize accumulating evidence supporting ferroptosis as a cell‐type‐specific regulator of vascular pathology. Rather than functioning as a uniform pathogenic mechanism, ferroptosis produces distinct consequences in macrophages, VSMCs, and ECs. In macrophages, it amplifies inflammation and necrotic‐core expansion; in VSMCs, it weakens contractile phenotype maintenance and fibrous‐cap integrity; and in ECs, it disrupts barrier function and facilitates early lipid infiltration. This cell‐type‐specific view helps reconcile apparently diverse findings in the field and provides a more precise framework for therapeutic development.

A key insight emerging from this synthesis is that ferroptosis in AS should be viewed primarily as a functional amplifier of cellular dysfunction, rather than merely a terminal death pathway. In macrophages, ferroptosis promotes inflammatory amplification, defective efferocytosis, and expansion of the necrotic core, thereby accelerating plaque progression and destabilization. In VSMCs, ferroptotic injury compromises mitochondrial metabolism, contractile phenotype maintenance, and extracellular matrix production, ultimately weakening the fibrous cap and increasing plaque vulnerability. In ECs, ferroptosis disrupts redox balance and membrane integrity, leading to barrier dysfunction, increased lipid permeability, and facilitation of early atherogenic events. These divergent outcomes indicate that the pathological meaning of ferroptosis is determined not only by the presence of iron accumulation, lipid peroxidation, or GPX4 inactivation, but also by the functional role of the affected cell population within the plaque.

This framework has important conceptual implications. It challenges the simplified assumption that ferroptosis is a binary therapeutic target that should be either globally inhibited or activated. Although ferroptosis inhibitors have provided important proof‐of‐concept evidence in experimental AS models, indiscriminate inhibition may not fully restore the specific cellular functions required for plaque stabilization. Preserving endothelial viability without restoring barrier integrity may be insufficient to prevent lipid infiltration. Reducing macrophage ferroptotic death without improving efferocytosis or inflammatory resolution may fail to limit necrotic core expansion. Similarly, blocking VSMC ferroptosis without maintaining contractile phenotype and extracellular matrix synthesis may not effectively stabilize the fibrous cap. Therefore, future therapeutic evaluation should move beyond general ferroptosis markers and incorporate cell‐specific functional endpoints, such as endothelial permeability, macrophage efferocytosis and polarization, VSMC contractile marker expression, collagen production, fibrous cap thickness, and necrotic core size.

This cell‐type–specific perspective also helps clarify why ferroptosis‐related mechanisms may appear heterogeneous or even contradictory across studies. Core ferroptotic features, including iron overload, lipid peroxidation, glutathione depletion, and impaired GPX4 activity, are shared among different vascular cell types. However, the upstream triggers and downstream consequences differ substantially. In macrophages, iron retention, inflammatory signaling, and defective lipid handling are closely linked to ferroptosis‐driven plaque progression. In VSMCs, mitochondrial dysfunction, glutathione metabolism, ferritinophagy, and phenotype switching are more directly related to fibrous cap integrity. In ECs, redox imbalance, barrier disruption, and lipid permeability are central to ferroptosis‐mediated vascular injury. Thus, ferroptosis should not be interpreted as a single linear pathway in AS, but as a modular stress‐response program whose pathological output depends on cellular identity and plaque stage.

Within this context, natural products and TCM‐derived compounds emerge as particularly attractive candidates for ferroptosis modulation in AS. However, their therapeutic implications should be interpreted critically. The pleiotropic actions of natural compounds are often regarded as a limitation because they complicate precise target attribution, dose optimization, and safety evaluation. Yet in a chronic and multifactorial disease such as AS, this multi‐target property may also represent a mechanistic advantage. Ferroptosis is closely intertwined with lipid metabolism, inflammatory signaling, mitochondrial dysfunction, iron handling, and redox imbalance. Therefore, agents capable of simultaneously regulating several of these processes may be more suitable for long‐term vascular protection than highly selective inhibitors targeting a single molecular node.

The key question is therefore not simply whether a natural product can suppress ferroptosis in general, but whether it can restore the dominant ferroptosis‐sensitive function of a specific vascular cell type. For ECs, effective natural compounds should be evaluated by their ability to preserve barrier integrity, reduce lipid permeability, and maintain redox homeostasis. For macrophages, therapeutic benefit should be assessed in terms of inflammatory resolution, iron handling, foam cell formation, efferocytosis, and necrotic core limitation. For VSMCs, the most relevant endpoints should include preservation of contractile phenotype, mitochondrial fitness, collagen synthesis, extracellular matrix stability, and fibrous cap integrity. This shift in evaluation criteria may help distinguish true cell‐type–aware ferroptosis modulation from nonspecific antioxidant activity.

From a translational standpoint, the proposed framework also implies that ferroptosis‐targeted therapy should be matched to plaque stage and cellular target. In early lesions, endothelial‐centered strategies may be most relevant for preventing barrier dysfunction and lipid entry. During lesion progression, macrophage‐centered approaches may be required to limit inflammatory amplification and necrotic core formation. In advanced plaques, VSMC‐preserving strategies may be particularly important for maintaining fibrous cap integrity and reducing rupture risk. Such stage‐ and cell‐type–matched intervention models would provide a more realistic basis for evaluating natural product–based therapies and may also explain why certain compounds show broad anti‐atherosclerotic effects despite acting through multiple molecular pathways.

Nevertheless, several translational challenges remain. Natural products often suffer from limited bioavailability, variable composition, unclear pharmacokinetic profiles, and insufficient dose–response characterization. Their multi‐target activities, while potentially advantageous, also make it difficult to determine which molecular events are essential for therapeutic efficacy. Moreover, because ferroptosis has different functional consequences across vascular cell types, systemic administration of anti‐ferroptotic agents may not achieve the desired cell‐specific effects. Advanced delivery systems, including plaque‐targeted nanocarriers, biomimetic platforms, and cell‐selective delivery strategies, may therefore be necessary to translate natural product–based ferroptosis modulation into clinically meaningful vascular protection.

In conclusion, ferroptosis should be interpreted as a central but context‐dependent driver of AS. Therapeutic strategies should therefore move beyond global ferroptosis inhibition and instead restore the most vulnerable ferroptosis‐sensitive function of each vascular cell type. Natural products and TCM‐derived compounds may support plaque stabilization by preserving endothelial barrier function, limiting macrophage‐driven inflammation and necrotic‐core expansion, and maintaining VSMC‐mediated fibrous‐cap stability. This cell‐type‐aware perspective provides a conceptual basis for developing more precise and potentially safer ferroptosis‐targeted interventions in AS.

4.1. Limitations and Perspectives

Despite growing evidence that ferroptosis contributes to AS, several limitations remain. First, many mechanistic insights are derived from in vitro systems or animal models that cannot fully reproduce the cellular diversity and spatial complexity of human atherosclerotic plaques. Second, ferroptosis is spatially and temporally heterogeneous: the same process may be protective or harmful depending on cell type, microenvironment, and disease stage. Third, ferroptosis intersects with other regulated cell death and stress‐response pathways, including apoptosis, autophagy, necroptosis, and inflammatory signaling. Disentangling these interactions remains difficult, and future studies should define how ferroptosis cooperates or competes with other death programs within the plaque microenvironment.

From a therapeutic perspective, although natural products and traditional Chinese medicine–derived compounds demonstrate promising anti‐ferroptotic effects across multiple vascular cell types, several challenges must be addressed before clinical translation. These include variability in compound composition, limited bioavailability, unclear pharmacokinetics, and the absence of standardized dosing strategies. Moreover, the pleiotropic nature of natural products, while advantageous for multi‐target modulation, complicates precise mechanism attribution and safety evaluation.

Looking forward, future research should prioritize the development of strategies that integrate cell‐type–specific ferroptosis modulation with advanced delivery technologies to enhance targeting precision and therapeutic efficacy. Biomimetic nanoparticles, exosome‐based systems, and plaque‐targeted carriers may offer feasible solutions for overcoming spatial heterogeneity within lesions. In parallel, high‐resolution spatial transcriptomics, single‐cell multi‐omics, and longitudinal imaging approaches will be essential for mapping ferroptosis dynamics during plaque initiation, progression, and regression.

More specifically, several testable hypotheses can be derived from the cell‐type–specific framework proposed in this review. First, endothelial ferroptosis may function primarily as an early driver of atherogenesis by increasing endothelial permeability and lipid infiltration, whereas macrophage ferroptosis may become more prominent during lesion progression by amplifying inflammation, impairing efferocytosis, and promoting necrotic core expansion. In contrast, VSMC ferroptosis may be most closely associated with advanced plaque vulnerability through loss of contractile phenotype, mitochondrial dysfunction, and extracellular matrix destabilization. These hypotheses could be tested using longitudinal atherosclerosis models combined with cell‐specific ferroptosis reporters, conditional deletion or activation of key ferroptosis regulators, and spatial mapping of lipid peroxidation, iron accumulation, and GPX4‐related antioxidant capacity in plaques at different disease stages.

Second, future studies should determine whether natural products exert genuinely cell‐type–preferential anti‐ferroptotic effects rather than acting as nonspecific antioxidants. For example, compounds that activate Nrf2/GPX4 signaling may be particularly relevant for preserving endothelial barrier integrity, whereas agents that regulate hepcidin–ferroportin signaling, ferritinophagy, or inflammatory polarization may preferentially restore macrophage homeostasis. In VSMCs, interventions targeting glutathione biosynthesis, mitochondrial iron handling, or ferritinophagy may be more closely linked to preservation of fibrous cap integrity. These assumptions should be validated by using EC‐, macrophage‐, and VSMC‐specific genetic models, single‐cell transcriptomics, spatial lipidomics, and ex vivo human plaque systems. Such approaches would help distinguish whether natural products merely suppress ferroptosis globally or instead restore the dominant ferroptosis‐sensitive function of each vascular cell type.

Third, the therapeutic value of natural products should be evaluated in a cell‐type–aware delivery context. A practical hypothesis is that plaque‐ or cell‐targeted delivery of natural product–based ferroptosis modulators may achieve greater plaque stabilization than systemic administration or indiscriminate ferroptosis inhibition. Macrophage‐targeted nanocarriers, endothelial‐protective delivery systems, or VSMC‐preserving biomimetic platforms could be compared in parallel to determine whether selective restoration of cellular homeostasis produces superior effects on plaque burden, necrotic core size, fibrous cap thickness, and endothelial barrier integrity. These experimental directions would move the field beyond descriptive associations and provide a clearer translational path for natural product–based ferroptosis modulation in AS.

In summary, translating ferroptosis research into effective AS therapies will require deeper understanding of context‐dependent regulation, intercellular crosstalk, and long‐term safety. Addressing these issues may enable rational design of ferroptosis‐targeted interventions, particularly those based on natural products, that restore vascular homeostasis and reduce cardiovascular risk.

Author Contributions

Writing – original draft preparation: Ziwei Wang and Xuchun Zhong. Investigation: Weiwei Peng. Writing – review and editing: Chaoming Zhou and Liqin Luo. Visualization: Juncong Huang and Jue Wang. Supervision: Yanrong Suo. Funding acquisition: Wenyun Zeng. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Wang Z., Zhong X., Peng W., et al., “Cell‐Type–Specific Regulation of Ferroptosis in Atherosclerosis: Mechanisms and Therapeutic Potential of Natural Products,” Cell Biochemistry and Function 44 (2026): e70264. 10.1002/cbf.70264.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.