Regulatory roles of bioactive lipids in vascular homeostasis and remodeling

Abstract

Bioactive lipids are low-abundance, rapidly acting signaling molecules that orchestrate vascular homeostasis and remodeling through a closed-loop cycle of synthesis, localization, receptor/effector sensing, and inactivation. This review delineates the major bioactive lipid classes – eicosanoids, lysophospholipids, sphingolipids, and sterol-derived mediators – linking their enzymatic pathways, transport mechanisms, receptor networks, and termination routes to vascular physiology and disease. Centered on vascular homeostasis and remodeling, we summarize the roles of bioactive lipids across atherosclerosis, aneurysms, hypertension, and thrombosis. Collectively, these findings underscore the pivotal role of bioactive lipid signaling in cardiovascular disease, suggesting that these pathways and receptors may serve as promising targets for diagnosis and therapy.

Lipids are hydrophobic or amphipathic biomolecules that play foundational roles in cellular architecture, energy metabolism, and signal transduction. Historically, lipids received less attention than proteins and nucleic acids. Several factors contributed to this imbalance. First, lipids exhibit high chemical heterogeneity. Their diverse classes, acyl chain lengths, degrees of unsaturation, and positional isomers create a molecular space far more complex than that of nucleotides or amino acids, complicating identification and quantification. Second, lipids have limited programmability. Because they lack direct genetic encoding, research depends on the indirect manipulation of metabolic enzymes, transporters, or receptors, which creates longer causal chains. Third, lipids faced a paradigm disadvantage. They exist outside the central dogma, meaning early molecular biology breakthroughs primarily benefited gene- and protein-centered inquiry. Finally, technical constraints hindered the field for decades, as highly specific and standardized methods for lipid detection and imaging were largely unavailable.

In recent years, this landscape has changed rapidly. Metabolomics and lipidomics, centered on biological mass spectrometry, now enable high-throughput and accurate quantification. Additionally, metabolic flux analysis and imaging mass spectrometry provide critical dynamic and spatial information. The standardization of databases and analytics, such as LIPID MAPS, has further improved annotation depth and cross-study comparability.

These advances have produced two cascading effects. First, researchers have discovered and systematically annotated vast numbers of novel or previously indistinguishable lipid species. Second, the essential roles of lipids in membrane organization, signal transduction, metabolic reprogramming, and inter-organelle communication are continually being revealed. These discoveries drive further methodological iteration and broader application. Consequently, lipid research has emerged as a major focus across the life sciences.

It is now widely accepted that lipids fulfill three fundamental roles. First, they serve as the structural building blocks of cellular membranes. Second, they act as a primary medium for energy storage and participate actively in energy metabolism. Finally, lipids function as signaling molecules that mediate a wide variety of signal transduction pathways. Lipid molecules that mediate signaling are collectively referred to as “bioactive lipids” (no universal abbreviation). Bioactive lipids act at low abundance, in a rapid and reversible manner, and possess specific receptors or effector targets to directly regulate cellular physiology. Their regulation can be conceptualized as a closed loop of “synthesis – transport (localization) – sensing – inactivation.” First, they are synthesized or remodeled in situ within distinct membranous compartments by specific enzymes. Next, lipid transport proteins deliver them to target locales, establishing locally high-concentration microenvironments. They then activate membrane receptors or directly modulate effector proteins and ion channels to amplify downstream signals. Finally, dedicated enzyme systems rapidly clear them via hydrolysis, re-esterification, or oxidation, ensuring signals are brief, reversible, and spatially constrained. This paradigm underpins the centrality of bioactive lipids in physiology and pathophysiology. In multiple organ systems, the cardiovascular system has been reported to be particularly susceptible to modulation by bioactive lipids. The following review focuses on the mechanisms by which bioactive lipids regulate vascular homeostasis, inflammatory responses, and thrombosis.

Classes of major bioactive lipids and their metabolic pathways

According to the LIPID MAPS classification, lipids are divided into eight major categories: fatty acyls (FA), glycerolipids (GL), glycerophospholipids (GP), sphingolipids (SP), sterol lipids (ST), prenol lipids (PR), saccharolipids (SL), and polyketides (PK). These categories are based on the chemical structure of lipids and their biosynthetic origins. FA are synthesized through acetyl-CoA chain elongation and are involved in membrane formation, energy storage, and signal transduction. GL include acylglycerols, alkylglycerols, and 1Z-alkenylglycerols, serving as key components in cellular membranes, while GP, characterized by a phosphate group esterified to glycerol, are essential for membrane stability and cellular signaling. ST and PR share a common biosynthetic pathway, with sterols playing a role in membrane stability and hormone synthesis, and prenols contributing to membrane function and regulatory processes. SP have an amino alcohol backbone and are critical for cell signaling, membrane structure, and regulation of cell death. SL consist of fatty acyl groups directly linked to a sugar backbone, playing a role in cell recognition and immune responses, distinct from glycolipids. PK are diverse metabolites derived from plants and microbes, with structural diversity and significant roles in natural products, including antibiotics and bioactive compounds. Bioactive lipids are present across all eight categories, but the bioactive members of FA, GP, SP, and ST are the most abundant and have been studied in greatest depth. This review will focus on these four lipid classes due to their significant biological roles in cellular processes, such as membrane stability, signaling, and regulation of metabolism.

Bioactive lipids in the fatty acyl family–eicosanoids

Fatty acyls refer to a broad class of lipids derived from fatty acids and their metabolites, encompassing free fatty acids and their activated forms such as acyl-CoA, acyl-carnitine, and multiple modified species (e.g., hydroxylation, ketone formation, epoxidation, peroxidation, nitration). Among these, eicosanoids constitute the most abundant and functionally diverse bioactive group. Because they are predominantly generated by the oxidation of polyunsaturated fatty acids (PUFAs), eicosanoids are also termed oxylipins.

The principal precursor of eicosanoids is arachidonic acid (AA), an ω-6 PUFA that is extensively esterified in membrane phospholipids and can be stored in lipid droplets. Endogenous AA is mainly released from membrane phospholipids by the phospholipase A2 (PLA2) family, including the Ca²⁺-dependent cytosolic PLA2 (cPLA2), Ca²⁺-independent PLA2 (iPLA2), and secreted PLA2 (sPLA2). Free AA is metabolized via three major pathways: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450), producing prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), lipoxins (LXs), hydroxyeicosatetraenoic acids (HETE), hydroperoxyeicosatetraenoic acids (HPETE), and epoxyeicosatrienoic acids (EETs), among other metabolites. These species mediate spatiotemporally specific signaling in inflammation and immunity, vascular tone and platelet function, pain and fever, and tissue repair. Dysregulated eicosanoid biosynthesis is closely associated with cardiovascular disease [1]. The main pathways of eicosanoid metabolism are shown in Figure 1.

Figure 1:

Metabolism pathways of arachidonic acid. The COXs metabolize AA to protanoids, prostacyclin, and thromboxane. The LOXs metabolize AA to leukotrienes and hydroxyeicosatetraenoic acids (HETEs). The P450 epoxygenases metabolize AA to midchain HETEs and four epoxyeicosatrienoic acid (EET) regioisomers. 5-HPETE, arachidonic acid 5-hydroperoxide; 5-LOX, 5-lipoxygenase; 5-HETE, 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid; 12(S)-HETE, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid; 15(S)-HETE, 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid; ALOX, arachidonate lipoxygenase; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; CYP450, cytochrome P450; DHET, dihydroxyeicosatrienoic acid; EET, epoxyeicosatrienoic acid; LTA4, leukotriene A4; LTB4, leukotriene B4; LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4, leukotriene E4; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGF2, prostaglandin F2; PGH2, prostaglandin H2; PGI2, prostaglandin I2; PGJ2, prostaglandin J2; TXA2, thromboxane A2; TXB2, thromboxane B2.

The COX pathway

Cyclooxygenases (COXs) constitute the rate-limiting enzyme system in AA metabolism and comprise the isoenzymes COX1 and COX2. Both possess dual catalytic activities: at the cyclooxygenase active site, AA is first converted to prostaglandin G2 (PGG2), which is then reduced to prostaglandin H2 (PGH2) at the peroxidase site. PGH2 is highly unstable and serves as a common intermediate. It is further transformed by terminal synthases into multiple mediators. Microsomal PGE synthase 1/2 (mPGES 1/2) and cytosolic PGE synthase (cPGES) produce PGE2 (prostaglandin E2). Hematopoietic and lipocalin-type PGD synthases (H PGDS and L PGDS) generate prostaglandin D2 (PGD2). PGF synthase (PGFS) yields prostaglandin F2α (PGF2α). Prostacyclin synthase (PGIS) forms prostaglandin I2 (PGI2). Thromboxane synthase (TXAS) produces thromboxane A2 (TXA2). The terminal product spectrum is determined largely by the expression and subcellular localization of terminal synthases. These synthases are spatially coupled to COX [2].

Prostaglandins signal via specific G protein-coupled receptors (GPCRs). PGE2 acts through EP1–EP4 (PGE2 receptors). PGD2 signals through DP1 and DP2 (PGD2 receptors). PGF2α signals through FP (prostaglandin F2α receptor). PGI2 signals through IP (PGI2 receptor). TXA2 signals through TP (thromboxane A2 receptor). The expression patterns of these receptors are specific to cells and tissues. These patterns shape the biological effects of prostaglandins, including the regulation of inflammation and immunity, nociception and fever, vascular tone and platelet function, and tissue repair and remodeling [3].

Within the vascular system, cell-specific coupling of enzymes determines their functional roles. In vascular endothelial cells, PGH2 is predominantly converted by PGIS into PGI2. This promotes vasodilation and inhibits platelet aggregation. In platelets, PGH2 is tightly coupled to TXAS. This rapidly generates TXA2, which drives aggregation and vasoconstriction. COX1 is primarily constitutive and maintains basal TXA2 production. It also supports homeostatic functions, such as gastrointestinal mucosal protection. COX2, on the other hand, is inducible by inflammatory cytokines, shear stress, and growth factors. It plays a key role in inflammation, pain, fever, and tissue repair. COX2 expression is low in quiescent vessels but markedly upregulated in activated endothelium, smooth muscle cells, immune cells, and diseased tissues (e.g., atherosclerotic plaques), while being essentially absent from platelets [4].

Newly formed prostaglandins are rapidly inactivated or further metabolized to confine signaling spatiotemporally. PGE2, PGD2, and PGF2α are first oxidized by 15 hydroxyprostaglandin dehydrogenase (15 PGDH/HPGD) to the corresponding 15 keto derivatives, followed by Δ13 reduction, β oxidation, and ω oxidation for stepwise clearance. Owing to intrinsic instability, PGI2 and TXA2 undergo non-enzymatic hydrolysis to 6 keto PGF1α and TXB2, respectively, and are subsequently metabolized and excreted. These stable metabolites are commonly used as surrogate indices of in vivo PGI2 and TXA2 biosynthesis. PGD2 can also undergo dehydration and isomerization to the PGJ2 series, ultimately forming the electrophilic 15d-PGJ2, a PPAR (peroxisome proliferator activated receptor)-γ activator. Bidirectional interconversion between PGE2 and PGF2α is mediated by the AKR1C (Aldo-Keto Reductase Family 1 Member C) family [3].

The LOX pathway

The lipoxygenase (LOX) pathway represents a key metabolic axis of AA beyond COX. The human/mammalian LOX family principally includes arachidonate lipoxygenase 5 (ALOX5), ALOX12, ALOX12B, ALOX15, ALOX15B, and ALOXE3. LOXs catalyze site specific insertion of molecular oxygen into the AA carbon chain to form the corresponding HPETEs, which are subsequently reduced intracellularly by peroxidases to hydroxylated products (HETEs), or further converted into leukotrienes (LTs) and lipoxins (LXs), among other mediators.

With assistance from 5-LOX activating protein (FLAP) at the nuclear membrane, 5-LOX converts AA to 5S HPETE and, via dehydration and cyclization, generates the unstable epoxide intermediate LTA4 (leukotriene A4). LTA4 is hydrolyzed by LTA4 hydrolase to yield LTB4 (leukotriene B4, a potent neutrophil chemoattractant and activator), or conjugated with glutathione by LTC4 (leukotriene C4) synthase (LTC4S) to produce the cysteinyl leukotriene (cysLT) LTC4, which is subsequently converted to LTD4 (leukotriene D4) and LTE4 (leukotriene E4). These cysLTs mediate bronchoconstriction, increased vascular permeability, and mucus secretion. 5S HPETE can also be reduced to 5 HETE and further oxidized to 5-oxo-ETE (5-oxo-eicosatetraenoic acid), which signals through the Oxoeicosanoid Receptor 1 (OXER1) to recruit eosinophils, contributing to allergy and eosinophil associated inflammation. In addition, through transcellular or sequential actions of 5-LOX and 12/15-LOX, LTA4/HPETE can be transformed into specialized pro-resolving mediators (SPMs), namely lipoxins (e.g., LXA4, LXB4), whose overall effects include suppression of neutrophil recruitment, promotion of efferocytosis/phagocytosis, and facilitation of inflammation resolution.

ALOX12 and ALOX15 are widely expressed in leukocytes, platelets, epithelial/epidermal cells, and smooth muscle, producing 12-HPETE and 15-HPETE, respectively, which are reduced to 12-HETE and 15-HETE. 12-HETE is frequently associated with platelet activation, vascular reactivity, and tumor related migration. 15-HETE functions as a subtype selective signaling molecule that participates in inflammation control and serves as a precursor for lipoxin biosynthesis. ALOX15B is enriched in monocytes/macrophages, favoring the production of 15S-HPETE and influencing foam cell formation and the inflammatory phenotype of atherosclerosis. ALOX12B and ALOXE3 are more involved in the epidermal barrier. Notably, ALOXE3 has lipid hydroperoxide isomerase activity, generating specific epoxy/ketone products that enhance signaling diversity.

Products of the LOX pathway exert biological effects through specific receptors with pronounced cell/tissue specificity. Key examples include as follows. LTB4 acts via BLT1 (high affinity) and BLT2 (BLT:leukotriene B4 receptor) receptors to promote neutrophil chemotaxis, degranulation, and neutrophil extracellular trap (NET) formation. Cysteinyl LTs (LTC4/LTD4/LTE4) signal through CysLT1 and CysLT2 to drive bronchial smooth muscle contraction, increased vascular permeability, and fibrosis related responses. 5-oxo-ETE engages OXER1 to regulate eosinophil recruitment. Lipoxins primarily act via formyl peptide receptor 2 (FPR2) to promote resolution, restrain excessive inflammation, and support tissue repair [3].

The CYP450 pathway

The cytochrome P450 (CYP450) pathway constitutes another key metabolic route of AA beyond COX and LOX, primarily generating diverse bioactive lipids via epoxidation and ω/ω-1 hydroxylation. CYP450 enzymes are predominantly localized to the endoplasmic reticulum, with additional presence in mitochondria, and are widely expressed across tissues including the liver, kidney, myocardium, vascular endothelium, and brain. In epoxidation reactions, the CYP2C and CYP2J subfamilies catalyze AA to form four EETs: 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. EETs can be hydrolyzed by soluble epoxide hydrolase (sEH/EPHX2) to dihydroxyeicosatrienoic acids (DHETs), typically accompanied by attenuated activity. Thus, sEH expression and activity critically determine the amplitude and duration of EET signaling. By contrast, in ω/ω-1 hydroxylation reactions, the CYP4A and CYP4F subfamilies convert AA into 20-HETE and its homologs (19/18/17/16-HETE).

EETs act through a multi-target network: they interact with nuclear receptors PPARα/γ, transient receptor potential channels (e.g., TRPV4), and candidate membrane receptor pathways to enhance endothelial nitric oxide production, modulate calcium signaling, and exert anti-apoptotic and anti-inflammatory effects. In contrast, 20-HETE tends to couple with Rho/ROCK, protein kinase C, and redox signaling, increasing calcium sensitivity and contractile responses in vascular smooth muscle, augmenting vascular tone, and associating with upregulated inflammation and oxidative stress. Overall, EET signaling generally confers vasoprotective and anti-inflammatory features, whereas 20-HETE signaling favors vasoconstrictive and pro inflammatory phenotypes. The two pathways form a dynamic balance across organs and pathological contexts, jointly determining outcomes in blood flow regulation, inflammatory responses, and tissue homeostasis [3], 5].

Bioactive lipids derived from other polyunsaturated fatty acids

PUFAs are classified into n-6 and n-3 families based on the position of the first double bond relative to the terminal methyl (ω/n). The n-6 PUFAs are exemplified by AA, and also include linoleic acid (LA) and dihomo γ linolenic acid (DGLA), which can give rise to bioactive lipids such as series 1 prostaglandins (PGs), hydroxyoctadecadienoic acids (HODE), and hydroxyeicosatrienoic acids (HETE). The n-3 PUFAs mainly comprise eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Owing to their structural similarity to AA, n-3 PUFAs can compete with AA for COX/LOX/CYP catalytic sites, thereby reshaping product spectra and downstream effects. In the COX pathway, n-3 substrates generate series 3 prostanoids/thromboxanes (e.g., PGI3, PGE3, TXA3), which are generally less potent than series 2 counterparts. In the LOX pathway, EPA/DHA yield series 5 leukotrienes and a class of specialized pro-resolving mediators (SPMs), including EPA derived resolvins E (RvE) and DHA derived resolvins D (RvD), protectins (PDs), and maresins (MaRs), which accelerate resolution by promoting efferocytosis/phagocytosis, attenuating neutrophil recruitment, and remodeling cytokine networks. In the CYP450 pathway, EPA/DHA produce epoxides such as Epoxyeicosatetraenoic acids (EEQs) and epoxydocosapentaenoic acids (EDPs) that exhibit vasodilatory, anti-inflammatory, and metabolic protective actions, subject to regulation by sEH.

Overall, n-3 PUFA derived mediators tend to display anti-inflammatory, pro-resolving, and cardioprotective phenotypes across multiple tissues. Compared with AA derived eicosanoids, they exhibit systematic differences in receptor selectivity, efficacy, and half-life, thereby eliciting similar or opposing biological effects in intercellular signaling and disease progression. This substrate competition and remodeling of product lineages provide an important molecular basis for how dietary fatty acid interventions modulate inflammation and cardiovascular risk [6].

Bioactive lipids of the glycerophospholipid family–lysophospholipids

GPs constitute a pivotal lipid class, featuring a glycerol backbone linked to fatty acyl chains, a phosphate group, and a headgroup. Canonical membrane GPs are diacyl species and, based on headgroup identity, are categorized into six major classes: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidic acid (PA). Lysophospholipids (LPLs) are monoacyl derivatives formed by removal of one fatty acyl chain from these parent GPs. They are less hydrophobic and readily shuttle between membranes and lipoproteins [7], 8]. LPLs represent the principal bioactive members within the GP family, endowed with pronounced capacities for membrane shape regulation and signal transduction. In human blood, the major LPLs include lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI), lysophosphatidylserine (LPS), and lysophosphatidylglycerol (LPG), with LPC being most abundant (approximately 200–500 μM), followed by LPE and LPA, whereas LPI, LPG, and LPS are present at lower levels [9].

The abundance of LPLs is coordinated by multiple enzymatic and non-enzymatic routes, and tightly coupled to re-acylation cycles. LPC can be derived from several sources. One is the deacylation of PC by phospholipase A2 (PLA2) in the Lands cycle. Another is acyl transfer by lecithin–cholesterol acyltransferase (LCAT) during HDL maturation. Additionally, LPC is generated by the hydrolysis of HDL-associated PC through endothelial lipase (EL) [10]. In addition, oxidative stress can elevate LPC via non enzymatic mechanisms [11]. Other LPL classes arise from their respective diacyl precursors through PLA1/PLA2 mediated deacylation, and are subsequently reacylated back to diacyl phospholipids by lysophospholipid acyltransferases (LPLATs) [12], participating in the Lands cycle. Notably, LPA can also be generated from LPC, LPS, or LPE via hydrolysis by autotaxin (ATX/ENPP2) [13]. The primary lysophospholipid metabolic pathways are shown in Figure 2A.

Figure 2:

Metabolism pathways of bioactive glycerophospholipids and sphingolipids. (A) Lysoglycerophospholipids biosynthesis pathway. Phospholipase A (PLA) catalyzes the hydrolysis of membrane phospholipids, releasing lysophospholipids such as lysophosphatidylcholine (LPC) and free fatty acids. Autotaxin (ATX), a secreted lysophospholipase D, subsequently converts LPC/Lyso-PS/LPE into lysophosphatidic acid. (B) Sphingolipid metabolism. De novo ceramide synthesis begins with the serine palmitoyltransferase (SPT) complex, which condenses palmitoyl-CoA and serine. Fatty acyl chains of defined lengths are incorporated by CERS1–6, followed by desaturation of the sphingoid backbone by DES1 or DES2. Ceramides serve as central precursors for complex sphingolipids such as sphingomyelin and can be degraded to sphingosine and sphingosine-1-phosphate (S1P). PC, phosphatidylcholine; LPC, lysophosphatidylcholine; PE, phosphatidylethanolamine; LPE, lysophosphatidylethanolamine; PS, phosphatidylserine; LysoPS, lysophosphatidylserine; PA, phosphatidic acid; LPA, lysophosphatidic acid; PI, phosphatidylinositol; LPI, lysophosphatidylinositol; PG, phosphatidylglycerol; LPG, lysophosphatidylglycerol; HDL-PC, high-density lipoprotein bound phosphatidylcholine; EL, endothelial lipase; LCAT, lecithin: cholesterol acyltransferase; LysoPLD, lysophospholipase D; ATX, autotaxin; PLA1/2, phospholipase A1 and/or phospholipase A2; PLA2, phospholipase A2; cPLA2α, cytosolic phospholipase A2; sPLA2, secretory phospholipase A2; PLA2-IIA, phospholipase A2 group 2A; PS-PLA2, phosphatidylserine phospholipase A2; CerK, ceramide kinase; CerS, ceramide synthase; CPP, ceramide phosphate phosphatase; DES1, dihydroceramide desaturase 1; FADS3, fatty acid desaturase 3; LPP, lipid phosphate phosphatase; SK, sphingosine kinase; Smase, spingomyelinase; SMS, sphingomyelin synthase; SPP, sphingosine phosphate phosphatase; SPT, serine palmitoyltransferase; SPTLC1, serine palmitoyltransferase long-chain base subunit 1; 3KSR, 3-ketosphinganine reductase.

LPLs exert actions through two principal manners. First, at the physicochemical level, their monoacyl “inverted cone” geometry modulates membrane curvature, fluidity, and microdomain organization, thereby influencing vesicle budding, membrane fusion, and receptor clustering. Second, at the signaling level, LPLs act via specific receptors and downstream pathways – for example, LPA engages lysophosphatidic acid receptors 1–6 (LPAR1–6) to regulate inflammation, permeability, and fibrosis, whereas LPS signals through GPR34 and other targets to shape immune cell responses [14].

Bioactive lipids of the sphingolipid family

SPs are built on sphingosine or dihydrosphingosine backbones, coupled to fatty acids of varying chain lengths and saturation and diversified polar headgroups, forming a highly heterogeneous set of structures and functions. Representative bioactive sphingolipids include ceramide (Cer), sphingosine (Sph), sphingosine 1 phosphate (S1P), and ceramide 1 phosphate (Cer1P).

Within the metabolic network, ceramide occupies a central hub, upstream connecting de novo synthesis and sphingomyelinase pathways, and downstream branching into sphingomyelin, glycosphingolipids, as well as the Sph/S1P and Cer1P arms [15]. Three major reversible routes operate. Cer is hydrolyzed by ceramidases (acid, neutral, or alkaline isoforms) to produce Sph and free fatty acid. Sph can then be reacylated back to Cer by ceramide synthases (CerS1–6) using acyl CoA. Additionally, Cer is phosphorylated by ceramide kinase (CERK) to form Cer1P. Cer1P can be dephosphorylated back to Cer by Cer1P phosphatases. In parallel, Sph is phosphorylated by sphingosine kinases (SphK1/2) to produce S1P, and S1P is dephosphorylated by S1P phosphatases (SPP1/2) to regenerate Sph, thereby feeding Cer resynthesis [16].

These reactions are spatially compartmentalized. Ceramide is primarily generated in the endoplasmic reticulum and transferred to the Golgi by ceramide transfer protein (CERT) for headgroup addition. CERK localizes to the Golgi membranes, where it produces Cer1P. SphK1 is enriched at the cytosol/plasma membrane and facilitates S1P export to the plasma via transporters like Spinster homolog 2 (SPNS2). In the plasma, S1P associates with albumin or HDL to establish blood–tissue gradients. SphK2 is located in the nucleus, mitochondria, and other compartments, contributing to compartmentalized signaling roles for S1P [17]. The sphingolipid bioactive lipid metabolic pathways are shown in Figure 2B.

In terms of signalling, S1P functions as a prototypical secreted lipid mediator that engages G protein coupled receptors S1PR1–5 to activate Gi/Gq/G12/13 pathways, modulating PI3K–Akt, ERK, RhoA/ROCK, and PLC (Phospholipase C)–Ca²⁺ signaling and thereby regulating endothelial barrier function, immune cell trafficking, smooth muscle contraction, and fibrosis. Cer1P can influence arachidonic acid mobilization and inflammatory mediator release through regulation of cPLA2 and putative receptor candidates (including membrane associated proteins). Recent studies have also identified ceramide sensing receptors, through which ceramide can signal via activation of GPCRs such as Cysteinyl Leukotriene Receptor 2 (CYSLTR2), P2Y Purinoceptor 6 (P2RY6), and FPR2 [18], 19].

Bioactive lipids of the sterol family

STs are a class of lipids with the cyclopentanoperhydrophenanthrene as a backbone. Under the definition that “bioactive lipids directly regulate receptors or signaling pathways,” cholesterol itself primarily serves as a membrane structural component and metabolic precursor and is therefore generally not classified as a bioactive lipid. Its derivatives – oxysterols, steroid hormones, and bile acids (BAs) – are canonical bioactive lipids that directly engage receptor and transcriptional signaling. This network can be conceptualized along four interconnected axes. The first axis is the de novo cholesterol biosynthetic pathway, which originates from acetyl-CoA and provides the necessary precursor supply. The second axis involves the oxysterol generating pathway, which is centered on multiple CYP450 enzymes. Third is the steroid hormone biosynthesis pathway, which is initiated within the mitochondria. Finally, the bile acid biosynthesis pathway mediates cholesterol disposal and the enterohepatic circulation. The sterol-derived bioactive lipid metabolic pathways are shown in Figure 3.

Figure 3:

Metabolism pathways of bioactive sterols. Synthesis of cholesterol begins with the transport of acetyl-CoA from within the mitochondria to the cytosol. The rate limiting step in cholesterol synthesis occurs at the 3-hydroxy-3-methylglutaryl-CoA reductase catalyzed step. Cholesterol serves as a fundamental precursor for various bioactive sterols, including steroid hormones, bile acids, and oxysterols. ACAT, acetyl-CoA acetyltransferase; HMGCS, HMG-CoA synthase; HMGCR, HMG-CoA reductase; MVK, mevalonate kinase; PMVK, phosphomevalonate kinase; MVD, diphosphomevalonate decarboxylase; FDPS, farnesyl diphosphate synthase; FDFT, farnesyl-diphosphate farnesyltransferase (more commonly called squalene synthase); SQLE, squalene epoxidase (also called squalene monooxygenase); LSS, lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase); DHCR7, 7-dehydrocholesterol reductase; AKR, aldo-keto reductase; CYP, cytochrome P450; HSD, hydroxysteroid dehydrogenase; STS, steroid sulfatase; SULT, sulfotransferase; SRD5A, steroid 5 alpha-reductase; StAR, steroidogenic acute regulatory protein; BSH, bile salt hydrolase; CA, cholic acid; HSDH, hydroxysteroid dehydrogenase; AMACR, α-methylacyl-CoA racemase; BACS, bile acid-CoA synthase; ACOX2, acyl-CoA oxidase 2; SCP2, peroxisomal thiolase 2; BAT, BA-CoA: amino acid N-acetyltransferase; UGT, UDP-glucuronosyltransferase; CH25H, cholesterol 25-hydroxylase.

Oxysterols

De novo cholesterol synthesis occurs in the cytosol and endoplasmic reticulum. Acetyl CoA is converted to mevalonate by 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase, and through multiple steps involving isopentenyl pyrophosphate, squalene, 2,3-oxidosqualene, and lanosterol, cholesterol is ultimately produced by 7-dehydrocholesterol reductase (DHCR7) [19]. Newly synthesized cholesterol undergoes site specific hydroxylation by particular CYP450 enzymes to generate signaling competent oxysterols. CYP27A1, expressed in the liver, macrophages, and vascular endothelium, catalyzes side chain hydroxylation at C27 (also referred to as C26) to form 27-hydroxycholesterol (27-HC), which can enter the bile acid biosynthetic pathway, act as an LXR ligand to promote cholesterol efflux, and exhibit tissue and concentration dependent selective estrogen receptor modulator-like effects in certain contexts [20]. Neuron specific CYP46A1 generates 24S-hydroxycholesterol (24S-HC), enabling cholesterol to cross the blood–brain barrier and to function as an LXR ligand in maintaining brain homeostasis [21]. 25-hydroxycholesterol (25-HC) is produced by cholesterol 25-hydroxylase (CH25H) under inflammatory induction. It can be converted by CYP7B1 into 7α,25-dihydroxycholesterol (7α,25-DHC), the endogenous ligand of the GPCR EBI2, thereby regulating immune cell migration and central nervous system inflammatory responses [22]. The sulfotransferase SULT2B1b converts 25-HC to its sulfate ester 25HC3S, attenuating its receptor activity and facilitating clearance [22]. These oxysterols directly interlink metabolism and signaling, constituting a key branch of bioactive lipids.

Steroid hormones

At the inner mitochondrial membrane, cytochrome P450scc (CYP11A1) cleaves the cholesterol side chain to produce pregnenolone, which is then converted to progesterone by 3β-hydroxysteroid dehydrogenase (HSD3B), forming the central hub of steroidogenesis. From this hub, three major downstream routes diverge. Glucocorticoid pathway: progesterone undergoes 17α hydroxylation by 17α-hydroxylase/17,20-lyase (CYP17A1) to yield 17α hydroxyprogesterone, which is then 21 hydroxylated by CYP21A2 to form 11 deoxycortisol, and finally converted to cortisol by 11β-hydroxylase (CYP11B1). Mineralocorticoid pathway: progesterone is first converted by 21 hydroxylase (CYP21A2) to 11 deoxycorticosterone (DOC), subsequently hydroxylated at C11 by CYP11B1 to corticosterone, and further processed by aldosterone synthase (CYP11B2) via sequential C18 hydroxylation and C18 oxidation to produce aldosterone. Androgen/estrogen pathway: pregnenolone is first 17α hydroxylated by CYP17A1 to 17α hydroxypregnenolone, then subjected to the 17,20 lyase reaction to generate dehydroepiandrosterone (DHEA). DHEA is converted to androstenedione by HSD3B, which is then reduced to testosterone by 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3). In select peripheral tissues, 5α-reductase (SRD5A) converts testosterone into dihydrotestosterone (DHT). In parallel, androstenedione is aromatized by aromatase (CYP19A1) to estrone. Testosterone is also aromatized by the same enzyme to estradiol. The interconversion between estrone and estradiol is mediated by the HSD17B family [23].

These products function as bioactive lipids that act through the receptor network comprising the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR), thereby coordinately regulating the stress response, water–electrolyte homeostasis, and reproductive function [24], 25]. GPCRs have been identified as membrane receptors for various steroid hormones. Professor Jinpeng Sun and his collaborators have previously discovered several GPCRs that act as membrane receptors for distinct steroid hormones. For example, they identified GPR133 as a membrane receptor for the androgen 5α-dihydrotestosterone (5α-DHT) [26], GPR97 as a membrane receptor for glucocorticoids [27], GPR64 as a receptor for the adrenal androgen dehydroepiandrosterone (DHEA) [28], and GPR126 as a membrane receptor for progesterone [29]. These findings revealed that adhesion GPCRs (aGPCRs) represent a specific GPCR subfamily responsible for recognizing steroid hormones, thereby reshaping the current understanding of steroid hormone signaling mechanisms.

Bile acids

BAs are the principal products for cholesterol disposal and function as key signaling molecules. Their biosynthesis proceeds via two branches: the classic (neutral) and the alternative (acidic) pathways. The classic pathway is initiated by the liver-specific CYP7A1. HSD3B7 performs the 3-oxo-Δ4 conversion. The presence or absence of 12α-hydroxylation by CYP8B1 determines the product routing. When 12α-hydroxylation occurs, cholic acid (CA) is produced. In its absence, chenodeoxycholic acid (CDCA) is formed. Both branches undergo side chain oxidation by CYP27A1 and peroxisomal β-oxidation to shorten the side chain to C24 bile acids, which are then conjugated with glycine or taurine in the liver before being secreted into bile. The alternative pathway begins with mitochondrial CYP27A1-mediated hydroxylation/oxidation of the side chain. This is followed by 7α-hydroxylation by CYP7B1. Through HSD3B7 and peroxisomal β-oxidation, this pathway predominantly generates CDCA, independent of CYP8B1 activity. In the intestine, conjugated bile acids are partially converted by the microbiota into secondary bile acids (e.g., deoxycholic acid, DCA, derived from CA; lithocholic acid, LCA, derived from CDCA) and are reclaimed through the enterohepatic circulation mediated by ASBT and OSTα/β [30].

Functionally, bile acids activate farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (TGR5). Hepatic/intestinal FXR suppresses CYP7A1 via small heterodimer partner (SHP) and the fibroblast growth factor 19 (FGF19)–fibroblast growth factor receptor 4 (FGFR4)/klotho beta (KLB) axis to impose negative feedback on de novo synthesis, while TGR5 responds more robustly to secondary bile acids. Together, these pathways maintain bile acid homeostasis and prevent toxic accumulation [30].

Bioactive lipids in vascular disease

Effects of bioactive lipids on atherosclerosis

Atherosclerosis (AS) is the most common pathological substrate of cardiovascular disease and the leading cause of myocardial infarction and ischemic stroke. Its progression is not a mere accumulation of lipids but a complex pathological process accompanied by endothelial dysfunction, chronic inflammation, infiltration of monocytes and macrophages, foam cell formation, phenotypic switching of vascular smooth muscle cells (VSMCs), and remodeling of the fibrous cap. Rupture of the fibrous cap, with subsequent platelet aggregation and thrombosis, often precipitates acute clinical events [24]. In recent years, “metabolism–immunity” crosstalk has been recognized as a key axis in disease progression, with bioactive lipids playing pivotal roles in inflammatory responses and vascular pathology [3]. The function and complex mechanism of bioactive lipids in atherosclerosis are shown in Figure 4.

Figure 4:

Function and complex mechanism of bioactive lipids in atherosclerosis. Bioactive lipids regulate the development of atherosclerosis including VSMCs proliferation, platelet aggregation, leukocyte infiltration and macrophage proinflammation. They exert their respective biological functions through their specific receptors. (Created with Figdraw). NF-κB, nuclear transcription factor-κB; ox-LDL, oxidized low-density lipoprotein; PG, prostaglandin; PGE2, prostaglandin E2; PGI2, prostacyclin; TP, TXA2 receptor; TXA2, thromboxane A2; VSMC, vascular smooth muscle cell; IP, PGI receptor; EP, PGE2 receptor; S1PR, S1P receptor; ER, estrogen receptor; TLR4, toll-like receptor 4; 27-HC, 27-hydroxy cholesterol; CYSLTR2, cysteinyl leukotriene receptor 2. (Created with www.figdraw.com)

Eicosanoids and atherosclerosis

In the COX pathway, PGD2 and PGE2 regulate vascular and immune cell functions through their specific receptors. Genetic ablation of PGD synthases (H-PGDS or L-PGDS) in AS models commonly results in increased macrophage infiltration in the aortic root, elevated inflammatory markers such as IL-1β and MCP-1, and greater plaque burden [25]. DP1 receptor signaling in endothelium/smooth muscle is generally protective, and its loss accelerates plaque formation [31], whereas DP2 is more proinflammatory and chemotactic. PGD2 and its metabolites (e.g., 15d-PGJ2) can activate PPAR pathways, with accumulating evidence pointing to PPARγ-mediated regulation of cell phenotype and inflammation [32], with effects that are cell- and stage-dependent. PGE2 is broadly pro-inflammatory and pro-atherogenic in macrophages and endothelium, but its actions vary by EP1–EP4 receptor subtype and cell context. EP2/EP4 modulate adhesion and chemotaxis across immune and vascular wall compartments [33], 34]. TXA2 promotes platelet activation and vasoconstriction via the TP receptor, whereas PGI2 signals through IP to raise cAMP, inhibiting platelet aggregation and inflammatory adhesion and thereby exerting vasoprotection [35].

Within the LOX pathway, products of 5-LOX, 12-LOX, and 15-LOX cooperate via multiple receptors and signaling axes to regulate vascular wall inflammation, remodeling, and plaque evolution. LTB4 is a prototypical proinflammatory leukotriene of the 5-LOX pathway. By activating BLT1 on VSMCs and triggering pathways such as IKK–NF-κB, it drives inflammatory phenotypes, proliferation, and migration in VSMCs while strongly chemoattracting monocytes and T lymphocytes into the intima, thereby amplifying focal inflammation [36], 37]. Reducing LTA4H activity to selectively lower LTB4 production (dose- and selectivity-dependent) alleviates plaque inflammation in rabbit atherosclerosis models [38]. In contrast to LTB4, the lipoxin LXA4 reduces immune cell infiltration, suppresses proinflammatory mediators, and promotes resolution, conferring protection on the arterial wall [39]. The 12-LOX product 12(S)-HETE activates NF-κB/MAPK signaling, enhances endothelial–monocyte interactions, promotes inflammatory responses and migration/proliferation of monocytes and VSMCs, and modulates macrophage phagocytosis/polarization, collectively accelerating vascular inflammation and atherosclerosis progression [40], 41]. The 15-LOX product 15(S)-HETE rapidly upregulates endothelial FGF-2 via the Src–EGR1 axis to promote microvessel formation. It also induces factors such as IL-6 to act paracrinally on VSMCs, stimulating their proliferation and migration [42], 43].

In the CYP450 pathway, EETs are generally protective. In vascular endothelium, EETs suppress the NF-κB pathway, lowering Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), and IL-6 expression and thereby reducing leukocyte adhesion and infiltration [44]. Inhibition of sEH increases the ratio of EETs to their diol products (DHETs). In animal models of atherosclerosis, sEH inhibitors markedly reduce plaque burden and inflammation [3], 45]. By contrast, 20-HETE, produced by CYP4A/4F, is vasoconstrictive and proinflammatory, often correlates with plaque burden or features of vulnerability, and is considered a candidate biomarker. Mechanistically, 20-HETE can potentiate SREBP2-related cholesterol metabolic pathways and impair cholesterol efflux (e.g., ABCA1-mediated), promoting foam cell-like phenotypic switching of VSMCs and driving atherosclerosis progression [46].

Lysophospholipids and atherosclerosis

During the initiation and progression of atherosclerosis, LPL metabolism and tissue distribution undergo marked remodeling. Concentrations, molecular species profiles, and spatial localization of LPLs change dynamically, closely linking to inflammation amplification, endothelial dysfunction, immune cell recruitment, and plaque remodeling.

LPC is the most abundant circulating LPL, predominantly bound to albumin, with the remainder associated with LDL/HDL. LPC plays a pivotal role in atherosclerosis by acting on vascular endothelial cells to mobilize Ca²⁺ upregulate growth factors and adhesion molecules, trigger release of inflammatory mediators, enhance oxidative stress, and promote apoptosis. In VSMCs, LPC induces Ca²⁺ currents, ROS generation, apoptosis, and COX-2 expression, and drives VSMC proliferation, migration, calcification, and production of plasminogen activator inhibitor-1 (PAI-1). LPC increases macrophage chemotaxis, enhances phagocytic function, and induces proinflammatory mediators. It also promotes macrophage uptake of oxLDL, leading to foam cell formation and accelerating plaque progression. Moreover, LPC augments proinflammatory cytokine production in macrophages and promotes polarization toward M1-like proinflammatory phenotypes via G2A-mediated signaling [47]. Mass spectrometry imaging further shows that LPC (18:0) content is 46 % higher in advanced human carotid plaques than in early lesions, with spatial distribution positively correlated with fibrotic area, suggesting that LPC not only drives inflammation but also coexists with fibrosis within plaques [48].

LPA is among the most bioactive lipid mediators within plaques. Its concentration is increased 2–3-fold in advanced human and murine atherosclerotic lesions relative to early lesions. Mass spectrometry imaging reveals enrichment of LPA (18:1) in necrotic cores and foam cell clusters of advanced human carotid plaques, with spatial distribution positively correlated with fibrotic area [48]. In Ldlr^−/− mice fed a high-fat, high-cholesterol Western diet, intestinal levels of unsaturated LPA correlate with aortic atherosclerosis severity. Dietary supplementation with unsaturated LPA or its precursor LPC (18:1) in mice induces a Western diet–like phenotype. Notably, the autotaxin (ATX) inhibitor PF-8380 markedly reverses the effects of LPC supplementation, indicating that LPC bioactivity is primarily mediated through the ATX-LPA axis [49].

Evidence regarding other LPLs in AS is relatively limited. Current data suggest that LPI activates GPR55 to promote endothelial activation and suppress autophagy: in an in vitro endothelial model, LPI upregulates GPR55 and ICAM1, and induces the long noncoding RNA LINC01235. The latter acts as a sponge for miR-224-3p and regulates RABEP1, thereby inhibiting the autophagy pathway and exacerbating adhesion molecule expression and inflammatory responses [50]. By contrast, LPS exerts bidirectional effects in macrophages: on one hand, it enhances the expression of CD36, MSR1, LOX1, and TLR4, promotes oxLDL uptake and cholesterol accumulation, and thus favors foam cell formation and pro-atherogenic changes. On the other hand, under LPS stimulation it can downregulate inflammatory mediators, and under unstimulated conditions it alleviates ER stress, indicating certain anti-inflammatory potential [51].

Sphingolipid bioactive mediators and atherosclerosis

Sphingolipid metabolites are closely associated with atherosclerosis, among which ceramide and S1P trigger multiple mechanisms that regulate AS initiation and progression. Ceramide, a central intermediate in sphingolipid metabolism, has pathogenic roles in plaque formation supported by clinical and experimental evidence. First, ceramide levels in plasma and atherosclerotic plaques positively correlate with disease severity [52]. Ceramide suppresses endothelial nitric oxide synthase (eNOS) activity and increases ROS generation. It inhibits cholesterol efflux transporters ABCA1 and ABCG1, thereby increasing cholesteryl ester deposition in macrophages and promoting foam cell formation [53]. Ceramide activates NF-κB signaling and the NLRP3 inflammasome in endothelial cells and macrophages, enhancing release of IL-1β and TNF-α and reinforcing proinflammatory macrophage phenotypes. Genetic ablation or pharmacologic inhibition of ceramide-responsive receptors CYSLTR2 and P2RY6 mitigates atherosclerotic phenotypes without altering plasma lipids [18]. Notably, biological effects differ by acyl-chain length: C16:0 and C18:0 ceramides are considered the most atherogenic subtypes, whereas very-long-chain species such as C24:0 may exert relatively protective effects in certain contexts [54]. This “fatty acyl chain length specificity” suggests that targeting specific CerS isoenzymes could enable precision therapeutics.

In contrast to ceramide’s largely proatherogenic actions, S1P functions are more complex. S1P is mainly carried by HDL in plasma and regulates vascular homeostasis via S1P receptors (S1PR1–5). Compared with healthy individuals, HDL from patients with coronary artery disease contains less S1P, and S1P loading can restore HDL’s protective effects on endothelium and VSMCs [55]. S1P enhances endothelial cell tight junction protein expression through activation of S1PR1, maintains vascular barrier integrity, and reduces LDL and inflammatory cell infiltration into the intima. It stimulates eNOS phosphorylation, promotes NO production, improves vasodilation, and inhibits platelet aggregation. S1PR1 signaling also suppresses endothelial adhesion molecules VCAM-1 and ICAM-1, thereby reducing leukocyte adhesion and subsequent extravasation. However, because S1PR1 augments chemotaxis of lymphocytes and natural killer (NK) cells, it can have proinflammatory and potentially pro-atherogenic effects under certain immune contexts. S1PR2 plays a central role in recruiting inflammatory macrophages: in S1pr2^−/−/ApoE^−/− double-knockout mice, IL-18 and IL-1β release is reduced, leading to impaired interstitial macrophage recruitment and diminished plaque and necrotic core formation. In vitro, S1PR2-deficient macrophages express less CD36 and scavenger receptors, exhibit increased cholesterol efflux, and reduced oxLDL uptake [56].

Sterol ester–related bioactive lipids and atherosclerosis

Atherosclerosis was initially viewed as a cholesterol deposition–driven disease, consistent with cholesterol being the central target of lipid-lowering therapy [57]. Beyond cholesterol itself, oxysterols also participate in AS initiation and progression. 27-HC has been observed to rise in tandem with plasma cholesterol and lesion progression in multiple human plaque studies and animal models, and is relatively enriched in advanced lesions. Functionally, 27-HC activates the TLR4/NF-κB signaling axis, promoting expression of proinflammatory mediators and MMP-9 in macrophages and other immune cells, thereby amplifying local inflammation and matrix degradation [58]. In addition, as a selective estrogen receptor modulator–like molecule, 27-HC antagonizes estrogen’s vasoprotective effects and enhances endothelial adhesion molecule expression through ER-associated pathways [59], 60]. On the other hand, 25-HC produced by macrophages in inflammatory contexts, can accumulate within coronary atherosclerotic lesions and is associated with inflammatory amplification and adverse vascular remodeling [61].

The steroid lipid family modulates atherosclerosis susceptibility and progression through nuclear and membrane receptor–mediated pathways that remodel lipid metabolism, inflammatory signaling, and vascular function across the immune–endothelial–smooth muscle network: estrogen exerts overall inhibitory effects, reflected by optimization of the lipoprotein profile (increased HDL, decreased LDL), reduction of LDL oxidation, suppression of endothelial adhesion molecules and chemokines, attenuation of monocyte adhesion/migration, and promotion of vasodilation [62]. Low androgen states are associated with increased risks of coronary artery disease (CAD), thrombosis, and myocardial infarction (MI). Androgen receptor (AR)-dependent upregulation of androgen-dependent tissue factor pathway inhibitor-related protein (ADTRP) suppresses endothelial adhesion and transendothelial migration. Animal studies suggest that physiological-range androgens are anti-atherogenic, although with some heterogeneity [63], [64], [65]. Glucocorticoid effects are context-dependent. While excess or dysregulated glucocorticoid levels are linked to higher risks, locally, they can be anti-inflammatory and suppress macrophage proliferation [66], [67], [68]. Aldosterone, acting through the mineralocorticoid receptor (MR), can accelerate early atherosclerosis (AS) and enhance plaque inflammation even at non-hypertensive levels, recruiting inflammatory cells via the placental growth factor (PlGF) pathway. Population-based and translational evidence supports its association with adverse outcomes, although the causal relationship with AS requires further clarification [69], 70].

Multiple lines of evidence indicate that bile acid synthesis, excretion, and receptor signaling jointly influence AS progression. At the population level, patients with coronary heart disease exhibit significantly lower fecal total bile acids and secondary bile acids (DCA and LCA) than controls, suggesting that restricted cholesterol clearance via the bile acid pathway is associated with CHD [71]. In contrast, within chronic kidney disease (CKD) cohorts, circulating DCA levels are not associated with the prevalence, incidence, or progression of coronary artery calcification, indicating that plasma levels of a single bile acid subtype may not reflect vascular calcification risk [72]. Mechanistically and therapeutically, genetic reduction of bile acid synthesis alters the bile acid pool composition, decreasing intestinal cholesterol absorption and apoB-containing lipoproteins, thereby attenuating atherosclerosis [73]. UDCA can dissolve cholesterol crystals, inhibit the NLRP3 inflammasome, and suppress plaque formation in ApoE^−/− mice [74]. LCA, via TGR5, inhibits dendritic cell activation and NF-κB, conferring innate immune anti-inflammatory potential [75].

Effects of bioactive lipids on aneurysms

Aortic aneurysms (AA) are characterized by localized vascular dilation, thinning of the vessel wall, and disruption of extracellular matrix architecture. The most severe complications involve aortic dissection and rupture, leading to massive hemorrhage and high mortality. The pathological process encompasses not only endothelial dysfunction but also chronic inflammatory cell infiltration, degradation of elastin and collagen matrices, vascular smooth muscle cell (VSMC) apoptosis and phenotypic switching, as well as vascular remodeling [76].

Fatty acyls and aneurysms

Eicosanoid pathways contribute to aneurysm progression. An observational clinical study reported that an increased proportion of AA in erythrocytes is associated with abdominal aortic aneurysm (AAA) prevalence, suggesting the potential of AA as a biomarker [77], 78]. Compared with healthy individuals, patients with AAA exhibit markedly elevated expression of COX2 and mPGES1 [79]. COX2 knockdown significantly reduces the incidence and severity of Ang II–induced AAA in mice. In AAA explant cultures, ruptured AAA tissue shows upregulated secretion of TXA2 and PGE2 compared with intact AAA tissue [80]. Both in vitro and in vivo studies have demonstrated that mPGES1 deletion or pharmacologic inhibition of PGE2 synthesis can attenuate oxidative stress and inflammation, thereby suppressing aneurysm growth [81], 82]. However, VSMC specific deletion of the EP4 receptor exacerbates AAA, underscoring the need to consider the ligand heterogeneity of EP4 signaling [83]. In a rat AAA model, the TXA2 inhibitor BM573 reduced aneurysm growth and decreased tissue expression of COX2, urokinase type plasminogen activator (uPA), and tissue plasminogen activator (tPA) [84]. In mouse models with Alox12 or Alox15 deletion, AAA development is significantly reduced [85]. Components of the 5-LOX pathway – 5-LOX/FLAP/LTC4S – are highly expressed in the vascular wall and thrombus cells of human AAA, and montelukast, a leukotriene receptor antagonist, can slow disease progression and lower rupture rates [86], 87]. rAAV mediated CYP2J2 overexpression, which elevates EET levels, has been shown to prevent AAA formation [88]. In addition, other polyunsaturated fatty acids modulate aneurysm pathology: dietary intake of EPA and DHA significantly lowers aortic expression of TNF α, MCP1, TGFβ, MMP2, MMP9, and VCAM1, suppresses aortic and macrophage mediated inflammation, and prevents the development of AAA [89]. However, the clinical benefits of EPA and DHA supplementation in patients still require confirmation in large trials.

Other fatty acids also play an important role in aortic aneurysm. Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome [90]. Nitro-oleic acid(NO2-OA) has been investigated to attenuate ascending aortic dilation and wall stiffening in Marfan syndrome mice by inhibiting the overactivation of ERK1/2, Smad2 and NF-κB in the aorta, thus reducing elastin fragmentation, cell apoptosis and collagen deposition induced by MMP2. Correspondingly, NO2-OA exerts a protective effect on the observable decrease of extracellular matrix degradation, inflammatory cytokine release, and macrophage infiltration in AAA model.

Lysophospholipids and aneurysms

Studies have reported decreased serum/plasma levels of LPC in patients with aortic dissection/aneurysm compared with controls [91], 92]. In Ang II–induced mouse models of AAA and human lipidomics analyses, glycerophospholipid metabolism is dysregulated, characterized by reductions in select LPC and LPE species. Mechanistically, LPA is a potent driver of VSMC phenotypic switching and pro fibrotic signaling. The membrane bound lipid phosphatase PLPP3 (also known as LPP3/PPAP2B) dephosphorylates LPA to reduce its activity. Inflammatory environment regulates PLPP3 via NF κB. Loss of PLPP3 in SMCs amplifies LPA signaling, promoting a fibroblast like transition and extracellular matrix remodeling, which – within specific models/time windows – correlates with reduced AAA expansion/rupture risk, yielding a net protective effect. However, LPAR subtype specificity is pronounced: LPAR4 deletion aggravates Ang II–induced dilation and mortality, indicating a vascular protective role for LPAR4 [93], 94].

Sphingolipid bioactive mediators and aneurysms

Clinical and experimental studies indicate that circulating S1P levels are generally reduced in AAA; in mouse models, the PPARα agonist fenofibrate elevates circulating S1P and slows AAA progression, suggesting therapeutic potential for upregulating the S1P axis [92]. In acute aortic dissection (AAD), metabolic disorders in sphingolipids are more pronounced in Stanford type A patients, with marked reductions in multiple sphingolipids (e.g., sphingosine and select ceramides), whereas changes in type B are less consistent or not significant [91].

Mechanistically, Ang II–induced AAA in mice and patient samples show elevated platelet ceramide and marked downregulation of alkaline ceramidase 1 (ACER1) in platelets. Ceramide accumulation augments platelet–leukocyte aggregation and vascular wall infiltration via the p38 MAPK pathway and promotes pro inflammatory cytokine secretion. Accordingly, enhancing platelet ACER1 mediated ceramide degradation exerts anti-inflammatory effects, suppressing platelet–leukocyte interactions and attenuating AAA onset and progression, highlighting the therapeutic potential of the ACER1/ceramide axis [95]. In addition, metabolomic and immunologic analyses reveal a positive correlation between ceramide levels and T cell infiltration in perivascular adipose tissue (PVAT) of AAA patients, suggesting tight coupling between local sphingolipid metabolism and remodeling of the immune microenvironment [96].

Ceramide metabolic disturbance plays an important role in thoracic aortic dissection (TAD). In an untargeted metabolomics research, it is found that sphingolipid, especially its core metabolite C18-ceramide, was significantly distinguished in TAD patients. The enhanced ceramide biosynthesis in macrophages within the TAD microenvironment could promote local immune activation, contributing to a more inflammatory and maladaptive tissue remodeling process [97]. Another research found that lyso-globotriaosylceramide (Gb3) inhibited the growth of fibroblasts, as well as their differentiation into myofibroblasts, and collagen expression. Then promoted development of ascending thoracic aortic aneurysm in Fabry disease. Lyso-Gb3 downregulated KCa3.1 channel expression, and these impairments could be rescued when activating the KCa3.1 channel or increasing intracellular Ca²⁺ concentration [98].

Sterol derived bioactive lipids and aneurysms

AAA patients typically exhibit elevated LDL-C and triglycerides with reduced HDL-C. Genome-wide association studies (GWAS) further support a role for lipid homeostasis in AAA, identifying loci such as PCSK9, APOE, and LDLR associated with risk [99]. From a sex biology perspective, men have a substantially higher AAA risk than women, implicating sex hormones; clinical data report that low serum testosterone in older men associates with increased AAA risk [100], whereas the relationship between estradiol and AAA varies across populations and methodologies, with inconsistent directions [101]. Mechanistically, 6β hydroxytestosterone (6β-OHT), a CYP1B1 derived testosterone metabolite, promotes AAA development in male mouse models [102]. Regarding oxysterols, AAA patients display pronounced ER stress and mitochondrial dysfunction, with elevated plasma 7-ketocholesterol (7-KC) and reduced 24-HC, 27-HC, and 7α-HC; 7-KC correlates positively with ER stress markers, suggesting links to intramural oxidative stress, apoptosis, and reduced mitochondrial biogenesis in AAA [103]. Oxysterols are also a common risk factor for TAA. In VSMCs derived from TAA, 7-KC and 25-HC induce ROS elevation and apoptosis partly independently of canonical caspase 3/p53/Bax pathways, indicating that oxysterols can trigger VSMC death through multiple ROS related routes, consistent with cellular loss and matrix degradation in aneurysms [104].

Converging evidence from population, animal, and mechanistic studies supports a pivotal “bile acids–receptor signaling–gut–vascular” axis in aneurysm pathogenesis. In intracranial aneurysm patients, bile acid metabolism is dysregulated; in ruptured cases, multiple glycine conjugated secondary bile acids are downregulated, suggesting disrupted antioxidant and inflammatory balance [105]. UDCA and tauroursodeoxycholic acid (TUDCA) protect the vascular wall via antioxidant and ER stress–inhibitory mechanisms, respectively: UDCA enhances VSMC Nrf2 activity, suppresses NOX subunit expression, reduces ROS, and decreases aortic dissection incidence [106]; TUDCA markedly attenuates Ang II–induced AAA expansion in ApoE/mice, lowering ER stress and apoptotic mediators such as GRP78/94 and CHOP [106]. Recent work further shows that pathogenic activation of intestinal FXR upregulates Cers2 and promotes the release of C20 ceramide, thereby enhancing macrophage MMP secretion and extracellular matrix degradation and UDCA mitigates AAD by inhibiting the intestinal FXR/Cers2 axis, reducing inflammation and matrix damage [107].

Effects of bioactive lipids on blood pressure

Hypertension is a major risk factor for various cardiovascular diseases, severely compromising the structural and functional integrity of the microcirculation and leading to increased peripheral vascular resistance, metabolic dysregulation, chronic kidney disease, and heightened sympathetic excitability. Experimental evidence indicates that the overarching pathological mechanisms associated with disease progression primarily include activation of the renin–angiotensin–aldosterone system (RAAS), intracellular Ca²⁺ overload, NO deficiency, oxidative stress, maladaptive ion channel remodeling, and VSMC depolarization.

Eicosanoids and hypertension

Eicosanoid pathway regulate vascular tone and the progression of hypertension as vasodilators or vasoconstrictors. In the COX pathway, PGE2 exerts bidirectional effects: via EP1/EP3 it enhances VSMC Ca²⁺ sensitivity to induce contraction and promotes tubular sodium reabsorption to raise blood pressure, whereas via EP2/EP4 it facilitates vasodilation and natriuresis to lower blood pressure [108]. PGD2 activates DP1 to promote endothelium dependent relaxation and suppresses VSMC phenotypic switching through the Epac1/Rap1/RhoA axis [3]. PGF2α is a potent vasoconstrictor that increases blood pressure through FP receptor activation. TXA2, through TP receptors, induces vasoconstriction and platelet aggregation, which increases hemodynamic load. At higher concentrations, TP receptors can also be activated by other prostaglandins (PGs), isoprostanes, and HETEs, triggering contraction [108]. In contrast, PGI2 induces vasodilation by activating IP receptors. Reduced PGI2 signaling is associated with pulmonary arterial hypertension. Inhaled PGI2 lowers pulmonary arterial pressure and resistance, with epoprostenol (Flolan/Veletri) being one of the first-line therapies [109], 110].

Within the LOX arm, selective ALOX12 inhibition effectively decreases 12 HETE production and lowers blood pressure in rats. ALOX12 activity correlates with VSMC hypertrophy, proliferation, and migration, while selective inhibition reverses adrenaline induced pathological features. ALOX15 has been implicated in hypertension progression across multiple animal models. Mechanistically, macrophage derived ALOX15 produces 12(S) HETE, which promotes vasoconstriction via endothelial TP and BLT2 receptors, thereby elevating blood pressure [111]. Targeted deletion of ALOX15 in macrophages can block PPARγ dependent hypertensive signaling [112].

In the CYP branch, 20-HETE is a potent vasoconstrictor that mediates eNOS uncoupling and reduces NO production, leading to endothelial dysfunction and hypertension [113]. In contrast, EETs confer antihypertensive effects through vasodilation, natriuresis, and blood pressure reduction. Genetic deletion of sEH in mice prevents EET degradation and mitigates renal injury and inflammation in salt sensitive hypertension [114].

Lysophospholipids and hypertension

Metabolomics studies have identified elevations of certain lysophospholipids, such as LPC (16:1), in the plasma of patients with hypertension [115]. LPC can induce eNOS uncoupling, increase ROS, and reduce NO bioavailability via ERK1/2 signaling, thereby impairing endothelium dependent relaxation [116], 117]. Genetic and functional evidence supports the involvement of the LPA receptor axis in hypertension. A 3′ flanking variant in LPAR1 is associated with essential hypertension and interacts with sleep deprivation. Mice deficient in LPAR1 are resistant to blood pressure elevation induced by sleep deprivation and to vasoconstriction similar to noradrenaline, suggesting that LPAR1 may be a susceptibility gene [118]. In the Dahl Iwai salt sensitive hypertension model, the LPA1 antagonist AM095 reduces proteinuria, improves renal function, and inhibits renal fibrosis under both preventive and therapeutic regimens, and demonstrates synergy with ACE inhibitors, providing renoprotection that is partly independent of its blood pressure lowering effects [119]. In vitro, LPG can cooperatively trigger VSMC intracellular Ca²⁺ overload through PLC/IP3 receptor–dependent ER Ca²⁺ release and extracellular Ca²⁺ influx, implicating its potential role in excitation–contraction coupling and vascular abnormalities associated with hypertension [120]. Additionally, studies on cardiac mitochondrial lipid homeostasis show that LPE supplementation elevates mitochondrial PE levels in aged myocardium, improves mitochondrial structure and function, and alleviates diastolic dysfunction, offering a lipid metabolic intervention strategy for Heart Failure with preserved Ejection Fraction (HFpEF), which commonly coexists with hypertension [121].

Sphingolipid bioactive lipids and hypertension

Sphingolipid bioactive lipids play pivotal roles in the development and progression of hypertension. Ceramides are elevated under hypertensive conditions and activate protein phosphatase 2A (PP2A), leading to eNOS dephosphorylation and inhibition, thereby inducing endothelial dysfunction and elevating blood pressure [122]. S1P exerts bidirectional regulation of vascular tone in a cell- and receptor subtype-dependent manner. In endothelial cells, S1P promotes endothelium-dependent relaxation by activating eNOS and increasing NO production via S1PR1/3 signaling. In vascular smooth muscle cells, S1P increases intracellular Ca²⁺ through S1PR2/3, activating calmodulin-dependent myosin light chain kinase and inducing contraction. Animal studies further suggest an inverse relationship between S1PR1 signaling and blood pressure. For instance, S1PR1 agonists (e.g., SEW2871) reduce angiotensin II–induced hypertension, while S1PR1 deletion in mice leads to elevated blood pressure. In anesthetized mice, the S1P/Sphk1/S1PR1 axis is essential for the acute hypotensive response [123]. Additionally, experimental hypertension is often associated with elevated plasma S1P, and global deletion of Sphk1 mitigates angiotensin II–dependent hypertension [55]. These findings suggest that increased S1P may serve as a compensatory negative feedback mechanism under hypertensive stress, with the net effect determined by cell context and receptor subtype engagement.

Sterol ester–related bioactive lipids and hypertension

Population and mechanistic studies indicate that hypertension is accompanied by remodeling of oxysterol and bile acid metabolism and its association with endothelial dysfunction: plasma LDL from hypertensive patients shows elevations of 7-ketocholesterol (7-KC), cholestane triol, and 5,6 epoxycholesterol derivatives, together with upregulation of endothelin-1 (ET-1), suggesting oxidative stress and impaired endothelial regulation [124]. Metabolomics evidence (LC-MS) further reveals increased levels of conjugated bile acids in the plasma of male hypertensive patients, indicating systemic alterations in sterol lipid–related metabolic networks within the hypertensive phenotype [125]. In mice, circulating 7α,25-dihydroxycholesterol (7α,25-DHC) activates GPR183 (EBI2) and promotes endothelial senescence and dysfunction via the cAMP/PKA/CREB pathway, implicating an oxysterol–receptor axis as a potential pathogenic node [126].

Effects of bioactive lipids on thrombosis

Thrombosis is a key pathological event in acute myocardial infarction, ischemic stroke, and peripheral arterial occlusion. Its essence lies in the interplay among excessive platelet activation, imbalance of the coagulation system, and vascular endothelial injury.

Eicosanoids and thrombosis

Eicosanoids occupy a central position in platelet function and arterial thrombosis. Within the COX pathway, platelet-expressed COX 1 converts AA to TXA2, which, via TP receptors, induces potent platelet aggregation and vasoconstriction, and is thus considered a major prothrombotic driver in arterial thrombosis. Aspirin irreversibly inhibits COX 1 and blocks TXA2 generation, significantly reducing the risks of myocardial infarction and ischemic stroke. It is a first line antiplatelet strategy for secondary prevention of atherosclerotic cardiovascular disease. However, its impact on hemostasis entails tradeoffs due to increased risks of systemic and intracranial bleeding [127]. In contrast to TXA2, PGI2 mediates antithrombotic effects by inhibiting platelets and inducing vasodilation via IP receptors. Some studies suggest that IP receptor activation upregulates sirtuin 1 and suppresses tissue factor expression, thereby conferring protection in thrombosis prone contexts, though this signaling cascade requires further validation across models and populations [128]. The effects of PGE2 on platelets are receptor subtype dependent: EP3 signaling promotes aggregation, whereas EP2/EP4 signaling inhibits activation, reflecting bidirectional regulation contingent on receptor repertoire [129].

Beyond COX products, the LOX axis also participates in platelet activation. Platelets are rich in 12 LOX, whose activity is critical for Fc receptor–mediated platelet activation [130]. Pharmacological evidence indicates that the potent 12 LOX inhibitor VLX 1005 suppresses human platelet activation in vitro and reduces arterial thrombosis in mice in vivo without significantly affecting physiological hemostasis, suggesting a potential “antithrombotic without increased bleeding” therapeutic window. This strategy currently resides in early clinical/translational stages [131]. Downstream mediators include 12(S)-HETE, which enhances thrombin–PAR4 signaling via GPR31 to promote platelet activation and arterial thrombosis [132]. Within the leukotriene spectrum, LTC4 – but not LTD4 or LTE4 – specifically activates murine platelets through CysLT2R [133]. Additionally, 20 HETE augments platelet aggregation and shortens bleeding time in animal models, suggesting relevance to stroke risk, although its causal significance in humans remains to be clarified [134].

Lysophospholipids and thrombosis

LPLs act in a cascade during thrombogenesis. At the early phase of receptor activation, PI in the platelet membrane is rapidly converted to LPI via the PLA2 pathway, indicating swift mobilization of LPLs in signal transduction [135]. In platelets, LPC induces oxidative stress and Ca²⁺ overload, leading to mPTP opening, mitochondrial membrane potential collapse, and PS exposure. This triggers platelet death and microvesicle release, thereby enhancing coagulability [136]. LPA promotes PS externalization in erythrocytes and the generation of procoagulant microvesicles – mechanistically linked to PKCζ activation and flippase inhibition – thus facilitating thrombin generation and increasing erythrocyte adhesiveness [137]. Concurrently, LPA elicits neutrophil extracellular trap (NET) formation through a PAD4 dependent pathway, providing a thrombogenic scaffold and conferring resistance to tPA. NETs, in turn, can reactivate platelets to release additional LPA, establishing a positive feedback loop [138].

Sphingolipid bioactive mediators and thrombosis

Platelets store abundant S1P and release it following thromboxane production, thereby further activating platelets via autocrine and paracrine routes and promoting thrombosis. S1P can enhance platelet aggregation and shape change both in vivo and in vitro, is essential for platelet biogenesis and proplatelet formation, and establishes a critical signaling link between hemostasis and inflammation. In addition, ceramide – another major sphingolipid – also regulates platelet function and thrombosis: when ceramide metabolic pathways are targeted by pharmacologic inhibition or genetic knockout, platelet degranulation, procoagulant activity, and thrombus formation are markedly impaired [139].

Sterol ester–related bioactive lipids and thrombosis

Regarding oxidized sterols, multiple oxysterols (e.g., 7-KC and 4-cholestenone) are elevated in erythrocytes of patients with COVID-19 and correlate with disease severity and thrombotic complications, suggesting that they may foster a prothrombotic milieu by inducing oxidative stress and eryptosis like changes [140].

With respect to steroid hormones, estrogens are clinically associated with increased risks of both arterial and venous thrombosis. Venous thromboembolism (VTE) often manifests within months of estrogen therapy initiation, although the precise molecular mechanisms remain incompletely defined [141]. Among progestins, high doses or specific formulations (e.g., norethisterone acetate, medroxyprogesterone acetate, depot medroxyprogesterone) are significantly associated with elevated VTE risk, underscoring a compound specific effect [142]. Along the androgen axis, testosterone therapy has been linked to a short term increase in VTE risk, with signals observed even in individuals without hypogonadism, pointing to potential nongenomic mechanisms [143]. Large population studies further indicate a time graded association between systemic glucocorticoid use and VTE risk, supporting a biological rather than purely confounded relationship [144]. In addition, for mineralocorticoids, aldosterone can, within minutes, enhance platelet aggregation, promote dense fibrin network formation, and suppress fibrinolysis via nongenomic signaling, effects that are partially reversible with mineralocorticoid receptor antagonists [145], 146].

Regarding bile acids, platelet TGR5 activation elevates cAMP/PKA and modulates AKT/ERK1/2 to inhibit platelet activation and spreading, with TGR5 deficiency enhancing thrombosis in mice [147]. DCA levels are reduced in patients with coronary artery disease, and DCA suppresses agonist induced platelet activation and thrombosis via platelet TGR5. These effects are attenuated when TGR5 is inhibited or deleted, whereas oral DCA, supplementation with DCA producing strains, or fecal microbiota transplantation from healthy donors suppress platelet hyperreactivity and thrombosis in atherosclerotic mice, supporting a protective “gut microbiota–bile acid–TGR5–platelet” axis in arterial thrombosis [148]. Moreover, glycoursodeoxycholic acid (GUDCA) strongly inhibits platelet activation, aggregation, and thrombosis without impairing basal hemostasis. This effect occurs through a mechanism involving diacylglycerol kinase (DGK) signaling. Long-term oral administration of GUDCA corrects obesity-associated DGK hyperactivation and hypercoagulability [148]. By contrast, within the hepatic milieu, certain bile acids (e.g., GCDCA, TCDCA) can directly amplify the procoagulant activity of the Tissue Factor (TF)-factor VIIa (FVIIa) complex and accelerate factor X (FX) activation, driving cholestasis associated intrahepatic coagulation – highlighting a tissue context–dependent, bidirectional action spectrum of bile acids on coagulation and platelet pathways [149].

Conclusion and perspective

In this review, we have organized bioactive lipids into major classes and mapped them onto a closed-loop regulatory framework of synthesis, transport (localization), sensing, and inactivation. We have covered representative families, including eicosanoids, lysophospholipids, sphingolipids, and sterol-derived mediators. For each of these lipid classes, we have outlined key enzymes, transport mechanisms, receptors or effector targets, and termination pathways, and have related these components to vascular homeostasis, inflammatory responses, and thrombosis. This synthesis of evidence spans across cellular systems, animal models, and clinical observations. Our emphasis has been on mechanistic links between lipid metabolism and receptor specificity within defined cell types and subcellular compartments, thereby explaining how low-abundance, rapid, and reversible lipid signals shape vascular pathophysiology.

In line with the evidence and framework synthesized in this review, we believe that future research on bioactive lipids should concentrate on four interrelated priorities:

1. Continued Discovery of Novel Signaling Molecules and Receptors

A central focus should be placed on the ongoing discovery of novel bioactive lipids and their corresponding receptors. It is critical that these discoveries be accompanied by rigorous mechanistic studies to establish clear causal pathways and define the mode-of-action of these signaling molecules. This research could lead to a more detailed understanding of how bioactive lipids influence specific cellular processes in different tissue types, helping to uncover new therapeutic targets.

2. Comprehensive Characterization of Spatiotemporal Metabolic Features

Future studies should aim to comprehensively characterize the spatiotemporal features of bioactive lipid metabolism, particularly at the level of specific cell types and subcellular compartments. This will require advanced imaging and analytical tools that allow resolution across different health and disease states, as well as understanding how lipid metabolism varies within different regions of tissues, particularly in vascular systems. This insight will be invaluable for understanding how lipids function in both normal physiology and pathological conditions, such as atherosclerosis, aneurysm formation, or thrombosis.

3. Systematic Screening of Bioactive Lipids in Large Clinical Cohorts

Large-scale clinical studies are needed to systematically screen key bioactive lipids in patient cohorts, including those with vascular diseases. By identifying robust lipid biomarkers and examining their correlation with disease progression, patient stratification, and clinical outcomes, such research could help improve diagnosis and guide personalized treatments. Additionally, these studies will improve reproducibility and interpretability across research settings, allowing for more reliable comparisons between clinical trials and laboratory findings.

4. Development of Targeted Therapeutics and Intervention Strategies

Finally, research should focus on developing targeted therapeutics and intervention strategies aimed at modulating bioactive lipid pathways. The goal should be to design strategies that can exert anti-thrombotic, anti-inflammatory, and vasoprotective effects, while maintaining safety and minimizing side effects. Targeting lipid metabolism may provide a novel avenue for addressing vascular diseases such as thrombosis, atherosclerosis, and inflammatory vascular disorders, offering new therapeutic options for patients. Furthermore, it is important that these therapeutic interventions be coupled with biomarkers to monitor their efficacy and safety in clinical settings.

By prioritizing these four interrelated directions, future research can advance both our fundamental understanding of bioactive lipids and their clinical application. This coordinated progress will not only help to unlock the full potential of bioactive lipids as therapeutic targets but also pave the way for precision medicine in the treatment of vascular diseases.