Abstract

Arachidonate 15-lipoxygenase (ALOX15) is a key member of the lipoxygenase family, catalyzing the oxidation of polyunsaturated fatty acids (PUFAs) to produce numerous biologically active lipid mediators. Recent studies have revealed that ALOX15 and its metabolites play a complex regulatory role in inflammatory responses. They are not only involved in inflammation resolution through the production of pro-resolving mediators but can also generate pro-inflammatory lipid signals that exacerbate inflammatory damage. Research utilizing gene knockout and transgenic animal models further indicates that ALOX15 contributes to the pathogenesis of various inflammation-related diseases, including neuroinflammation, atherosclerosis, asthma, rheumatoid arthritis, and metabolic inflammatory diseases. This article systematically reviews the current understanding of the role of ALOX15 in inflammation-associated diseases.

1 Introduction

Chronic inflammation-related diseases, such as atherosclerosis, asthma, inflammatory bowel disease (IBD), and rheumatoid arthritis (RA), constitute a major global health burden. Their continuously rising incidence and disability rates place a significant strain on healthcare systems (1). The common core of these diseases lies in the failure of the body’s inherent inflammatory response to be terminated in a timely and effective manner, thereby transforming from a protective process into sustained tissue damage (2). In this complex pathological process, lipid mediators derived from polyunsaturated fatty acids (PUFAs) play a crucial role. Acting as precise chemical messengers, they are not only responsible for the initiation and amplification of inflammation, more importantly, govern the active resolution of inflammation and the initiation of tissue repair. Their metabolic balance directly determines the progression and outcome of the inflammatory response (3–5).

Arachidonic acid (AA) is an essential PUFAs and serves as the primary precursor for eicosanoids, which in addition to their roles in various physiological functions, are implicated in numerous diseases, including atherosclerosis, diabetes, and neurological disorders. AA is metabolized through three major enzymatic pathways: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 monooxygenase (cytochrome P450) (6, 7). Consequently, a wide range of molecules targeting the bio-oxidation process of AA have been developed into clinical therapeutics. Among them, the COX pathway, targeted by classical nonsteroidal anti-inflammatory drugs (NSAIDs) and primarily responsible for generating mediators such as prostaglandins and thromboxanes, has long been a focal point in anti-inflammatory treatment (8). In parallel, the LOX pathway, predominantly governed by the lipoxygenase family, has gained increasing recognition for its biological significance.

Lipoxygenases (LOXs) are non-heme iron-containing dioxygenases that catalyze the stereospecific peroxidation of PUFAs, generating a series of bioactive lipid mediators. Typical products include various hydroperoxy PUFAs and leukotrienes (LTs). These lipid mediators primarily regulate the responsiveness, proliferation, and differentiation capacities of various cell types, playing significant roles in anti-infection, oncology, and inflammation, among other processes (9). In humans, there are six known functional LOX genes (ALOX5, ALOX12, ALOX12B, ALOX15, ALOX15B, ALOXE3), as shown in Table 1. They are conventionally designated “ALOX” for arachidonate lipoxygenases. All ALOX genes are sequentially arranged within a gene cluster without overlapping each other (10).

Human LOXsMain substratesMain productsTissue distributionReferencesAL0X5Arachidonic acid5(S)-HpETEGranulocytes, monocytes/macrophages, mast cells, dendritic cells and B lymphocytes(11)AL0X12Arachidonic acid12(S)-HpETEPlatelets and their precursors, megakaryocytes, keratinocytes and tumor cells(12)AL0X12BArachidonic acid12(R)-HpETESkin and hair follicles(13)Linoleic acid9(R)-HpODE(14)AL0X15Arachidonic acid15(S)-HpETE
12(S)-HpETEImmune cells and epithelial cells(15)Linoleic acid13(S)-HpODE(16)Docosahexaenoic acid17(S)-HpDHACorneal epithelium and brain tissue(17)AL0X15BArachidonic acid15(S)-HpETEHair roots, prostate, lungs, skin and corneas(18)Linoleic acid13(S)-HpODE(19)AL0XE3Arachidonic acid12(R)-HpETEEpithelial cells of the skin, tongue and stomach(3)Linoleic acid9(R)-HpODE(20)

Human LOX isozymes, their substartes, products and tissue distribution.

HpETE, Hydroperoxyeicosatetraenoic acid; HpODE, Hydroxydocosahexaenoic acid; HpDHA, Hydroperoxydocosahexaenoic Acid.

Among these, ALOX15 has garnered particular attention due to its unique substrate preference and product diversity. It mediates the dehydrogenation and subsequent oxygenation of AA to produce both 15-hydroperoxyeicosatetraenoic acid (15-HpETE) and 12-HpETE in a ratio of approximately 9:1 (21), which can be further metabolized into lipoxins (LX), hepoxilins (HX) and eoxins (EX) with diverse biological effects (22, 23). However, the functional properties of ALOX15 exhibit marked species-specific differences that must be considered when interpreting preclinical data. While human ALOX15 predominantly oxygenates AA to 15-HpETE, the murine ortholog (often termed leukocyte-type 12-LOX) primarily generates 12-HpETE (24, 25). This divergence in catalytic specificity, driven by targeted enzyme evolution during primate development (10), has profound implications for the translational relevance of findings obtained from conventional rodent models and necessitates careful consideration when extrapolating animal data to human pathophysiology.

Importantly, in-depth research has revealed a thought-provoking central paradox: ALOX15 can exhibit both pro-inflammatory and anti-inflammatory effects in inflammatory diseases. On one hand, it has been reported to exacerbate the progression of diseases such as atherosclerosis and asthma through mechanisms like oxidizing low-density lipoprotein (LDL) and generating pro-inflammatory lipids (15, 26);On the other hand, due to its capacity to synthesize pro-resolving mediators, it demonstrates clear protective roles in conditions like ischemic brain (27, 28).In summary, the relationship between ALOX15 and inflammation-related diseases is highly complex. This seemingly “contradictory” dual role precisely reflects the context-dependent functionality of ALOX15, making it a key challenge and hotspot for understanding precise inflammation regulation and developing novel therapeutic strategies.

Therefore, this review aims to systematically delineate the spectrum of roles played by ALOX15 across various inflammation-related diseases, delve into its functions and microenvironmental determinants, as well as comprehensively evaluate the potential and challenges of targeting ALOX15 and its downstream pathways as a therapeutic strategy, thereby providing a theoretical foundation for the development of novel treatment paradigms.

2 Biological characteristics and inflammatory regulatory functions of ALOX152.1 Enzymatic basis and key metabolites of ALOX15

ALOX15 is constitutively expressed in reticulocytes, eosinophils, dendritic cells, macrophages, and epithelial cells (29, 30). Its expression is regulated by multiple factors including cytokines (IL-4, IL-5, and IL-13), hypoxia, oxidative stress, and epigenetic modifications (31–33). ALOX15 possesses a C-terminal domain essential for its catalytic activity and an N-terminal β-barrel domain. It is generally localized in the cytoplasm, but can undergo membrane translocation in the presence of factors such as Ca2+, significantly enhancing its apparent enzymatic activity (34). The primary physiological substrates of this enzyme are AA, linoleic acid (LA) and docosahexaenoic acid (DHA) (35). Details are shown in Figure 1.

Fatty acid substrates and metabolites of human ALOX15. ALOX15 metabolizes arachidonic acid (AA) to generate 12(S)-HpETE and 15(S)-HpETE, which are further converted to their respective hydroxides, 12(S)-HETE and 15(S)-HETE, respectively. 12(S)-HpETE, 15(S)-HpETE and 15(S)-HETE can also be converted to other lipid mediators such as lipoxins (LX), hepoxillins (HX), trioxillins (TX), eoxins (EX). Docosahexanoic acid (DHA) is metabolized by ALOX15 into 17(S)-hydroperoxydocosahexanoic acid (HpDHA), which is further metabolized to form resolvins (RV) and protectin Ds (PD). ALOX15 metabolizes linoleic acid (LA) to generate 13(S)-hydroperoxyoctadecaenoic acid (13(S)-HpODE), which is subsequently converted to 13(S)-hydroxyoctadecaenoic acid (13(S)-HODE).

It primarily catalyzes the formation of 15(S)-HpETE and 12(S)-HpETE from AA. These products are subsequently reduced by cellular glutathione peroxidases to their corresponding hydroxyl analogues, namely 15(S)-HETE and 12(S)-HETE (22). 15(S)-HpETE and/or 15(S)-HETE can be further metabolized into various bioactive products, such as lipoxins (LXs), hepoxillins (HXs), and eoxins (EXs). LXA4, LXB4, aspirin-triggered (AT)-LXA4, and AT-LXB4 are a class of anti-inflammatory mediators that contribute to resolving inflammatory responses and inflammatory diseases in animal models (35). HX isomers, such as HXA3 and HXB3, are involved in regulating inflammatory responses and insulin secretion (36). EXs (EXC4, EXD4, and EXE4) exhibit pro-inflammatory effects and have been implicated in severe asthma and allergic reactions (37). 12(S)-HpETE and/or 12(S)-HETE bind to and activate G protein-coupled receptor 31 (GPR31) and the BLT2 (38).They can also be metabolized to HXA3 and HXB3, which are subsequently converted into their respective trihydroxy metabolites, such as trioxilin A3 (TXA3) and TXB3. These metabolites induce vasodilation, promote pain perception, reverse oxidative stress, and stimulate insulin secretion in various animal model systems (39).

ALOX15 can also efficiently catalyzes DHA, generating various lipid mediators with important biological functions. Initially, ALOX15 oxidizes DHA to 17S-hydroperoxy-DHA (17S-HpDHA), with a catalytic efficiency comparable to that for AA, confirming DHA as an effective physiological substrate of this enzyme (17). Subsequently, 17S-HpDHA can further serve as a substrate for ALOX15, undergoing a second oxidation reaction to form the key intermediates 17S-epoxy-DHA and 17(S)-hydroxy-DHA (17S-HDHA). Among these, 17S-epoxy-DHA has been confirmed as a direct precursor in the biosynthesis of protectin D (PD), while 17-hydroxy-DHA is considered a critical intermediate in the resolvins (RV) synthesis pathway (40). These products play key roles in inflammation resolution, immune regulation, inhibition of platelet aggregation, and modulation of synaptic plasticity (17).

In addition, ALOX15 can also catalyze LA to produce 13(S)-hydroperoxyoctadecadienoic acid (13-HpODE) and 13-HpETE (41). Studies have shown that 13(S)-HpODE binds to PPAR-delta, reduces its activation and expression, thereby promoting apoptosis in colorectal cancer cells (16). In conclusion, the relationship between ALOX15 and inflammation-related diseases is complex and context-dependent. Positioned at a critical node in PUFA metabolism, ALOX15 generates downstream products with both pro-inflammatory and anti-inflammatory activities, which underpins its dual role in pathology.

2.2 Pro-inflammatory effects of ALOX15

A growing body of research has confirmed the pro-inflammatory effects of ALOX15 and its metabolites (42, 43). Firstly, they have the capacity to directly recruit and activate inflammatory cells. Both 12-HETE and 15-HETE act as potent chemokines that directly attract and activate neutrophils, eosinophils, dendritic cells, macrophages, and mast cells. These compounds not only facilitate the recruitment and infiltration of these cells into sites of inflammation but also enhance the adhesive properties and degranulation processes of inflammatory cells, thereby significantly amplifying the inflammatory response (4, 44). For instance, studies have shown that ALOX15 promotes the migration of eosinophils and neutrophils to sites of inflammation, which is a key feature in the progression of chronic rhinosinusitis with nasal polyps (45, 46). Overexpression of ALOX15 in airway epithelial cells can induce the release of chemokines such as macrophage inflammatory protein-1α/β (MIP-1α/β), regulated on activation, normal T cell expressed and secreted (RANTES), and interferon gamma-induced protein 10 (IP-10), thereby significantly promoting the chemotaxis of immature dendritic cells (30). This recruitment of antigen-presenting cells is crucial, as it bridges the innate and adaptive immune responses. The resulting influx of dendritic cells, together with the direct recruitment of granulocytes, creates a microenvironment that favors the development of Th2 responses. This amplifies the production of IL-4, and form a positive feedback loop that locks the tissue into a state of persistent type 2 inflammation (47).

Additionally, 12-HETE and 15-HETE can activate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling axis, triggering the phosphorylation and activation of a series of downstream transcription factors. This ultimately drives the upregulation of gene expression for key pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as chemokines like monocyte chemoattractant protein-1 (MCP-1) (48). On the other hand, these lipid mediators can also target the nuclear factor kappa B (NF-κB) pathway by promoting the phosphorylation and degradation of its inhibitory protein (IκBα) or activating the upstream IκB kinase (IKK) complex. This leads to the dissociation and nuclear translocation of NF-κB transcription factor family members, thereby broadly inducing the expression of numerous genes involved in inflammation, cell survival, and proliferation (43, 49). This synergistic activation of central signaling pathways enables ALOX15-derived products to efficiently integrate and amplify inflammatory signals from various intracellular and extracellular stimuli, forming a powerful positive feedback loop. This mechanism plays a crucial role in the initiation and persistence of chronic inflammatory diseases.

More importantly, recent studies emphasize that ferroptosis is also recognized as a significant mechanism in inflammation (50). The expression of ALOX15 and related enzymes (such as PEBP1) promotes lipid peroxidation and the production of 15-hydroperoxyeicosatetraenoic acid-phosphatidylethanolamine (15-HpETE-PE), a key ferroptosis marker, which enhances inflammation by amplifying the activation of inflammatory pathways (51). The study by Yang et al. (52) demonstrated that the Th2-type cytokine IL-13 induces ferroptosis in bronchial epithelial cells by inhibiting the expression of glutathione peroxidase 4 (GPX4) and SLC7A11, thereby reducing glutathione (GSH) levels. This process not only leads to the accumulation of lipid peroxides but also triggers the release of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and reactive oxygen species (ROS) from epithelial cells, directly driving airway inflammation. Building on this, Kagan’s team revealed that ALOX15-mediated lipid peroxidation is closely associated with acute asthma exacerbations, leading to the hypothesis that ALOX15-regulated ferroptosis in bronchial epithelial cells may underlie this phenomenon (53). This concept establishes a mechanistic link between ALOX15 enzymatic activity and IL-13-triggered ferroptosis. Shah et al. (54) demonstrated that ferroptosis cells potently activate macrophages, prompting the release of substantial pro-inflammatory mediators. Concurrently, the lipid peroxides and arachidonic acid-derived inflammatory mediators generated during ferroptosis exacerbate the inflammatory cascade. Synthesizing these findings, a coherent mechanistic axis emerges: IL-13 activates ALOX15 and inhibits GPX4, leading to ferroptosis in bronchial epithelial cells, which in turn activates macrophages and releases mediators, thereby perpetuating airway inflammation. The key metabolites and mechanisms involved in pro-inflammatory responses are summarized in Figure 2 and Table 2.

ALOX15 and its key metabolites in inflammation versus resolution. Pro-inflammatory mediators produced by Alox15 include 12-HETE, 15-HETE, 15-HpETE-PE, and eoxins (EXC4, EXD4, EXE4), which promote chemotaxis, activation of inflammatory cells, MAPK/ERK or NF-κB signaling, ferroptosis, and Th2 immune amplification. Anti-inflammatory mediators such as lipoxins (LXA4, LXB4), resolvins (RvD1, RvD2, RvE1, RvE2), protectins (PD1, NPD1), and 13(S)-HODE inhibit inflammatory cell migration, induce M2 macrophage differentiation, reduce NF-κB-driven cytokines, and suppress innate immunity overactivation. The balance between these opposing mediators determines the outcome of inflammation (progression vs. resolution). 12-HETE, 12-hydroxyeicosatetraenoic acid; 15-HETE, 15-hydroxyeicosatetraenoic acid; 15-HpETE-PE, 15-hydroperoxyeicosatetraenoic acid-phosphatidylethanolamine; Alox15, arachidonate 15-lipoxygenase; EXC4, eoxin C4; EXD4, eoxin D4; EXE4, eoxin E4; LXA4, lipoxin A4; LXB4, lipoxin B4; RvD1, resolvin D1; RvD2, resolvin D2; RvE1, resolvin E1; RvE2, resolvin E2; PD1, protectin D1; NPD1, neuroprotectin D1; 13(S)-HODE, 13(S)-hydroxyoctadecadienoic acid; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor kappa B; Th2, T helper type 2; M2, alternatively activated macrophages.

MetaboliteChemical StructureSubstratePrimary Receptor(s)Biological FunctionReferencesPro-inflammatory mediators15-HETEC20H32O3 (Structure: 20:4, 15-OH)AAPPAR-γ
(partial agonist)(7)12-HETEC20H32O3 (Structure: 20:4, 12-OH)AAGPR31(38)EXC4C30H47N3O9S (Containing glutathione group)AACysLT1 receptor(37)EXD4C25H40N2O6SAACysLT1 receptor(37)EXE4C22H36O6SAACysLT1 receptor(37)15-HpETE-PEPhosphatidylethanolamine esterified 15-HpETEAA-PEmembrane disruption(53)Anti-inflammatory mediatorsLXA4C20H32O5 (Structure: 5S,6R,15S-triHETE)AAFPR2/ALX

Inhibits neutrophil chemotaxis;

Promotes macrophage efferocytosis;

Reduces NF-κB activation.

(82)LXB4C20H32O5 (Structure: 5S,14R,15S-triHETE)AABLTs(83)RvD1C22H32O5 (Structure: 7S,8R,17S-triHDoHE)DHAGPR32(human),
FPR2/ALX (murine)

Limits neutrophil infiltration;

Enhances macrophage phagocytosis;

Promotes tissue regeneration.

(84)RvD2C22H32O5DHAGPR18(84)RvE1C20H30O5 (Structure: 5S,12R,18R-triHETE)EPAChemR23,
BLT1 (antagonist)

Reduces inflammation;

Promotes resolution;

Organ protection.

(64)PD1/NPD1C22H34O4 (Structure: 10R,17S-diHDoHE)DHAGPR37

Neuroprotection; anti-apoptotic;

Promotes tissue regeneration;

Reduces oxidative stress.

(85)13(S)-HODEC18H32O3 (Structure: 18:2, 13-OH)LAPPAR-γ(86)

Key ALOX15-derived lipid mediators, their chemical structures, receptors, and biological functions.

HETE, Hydroxyeicosatetraenoic acid; HpETE, Hydroperoxyeicosatetraenoic acid; HODE, Hydroxyoctadecadienoic acid; PE, Phosphatidylethanolamine; AA, Arachidonic acid; DHA, Docosahexaenoic acid; LA, Linoleic acid; EPA, Eicosapentaenoic Acid; PPAR-γ, Peroxisome proliferator-activated receptor gamma; GPR31, G protein-coupled receptor 31; CysLT1, Cysteinyl leukotriene receptor 1; FPR2/ALX, Formyl peptide receptor 2/Lipoxin A4 receptor; GPR32, G protein-coupled receptor 32; GPR18, G protein-coupled receptor 18; ChemR23, Chemerin receptor 23; BLT1, Leukotriene B4 receptor 1; GPR37, G protein-coupled receptor 37.

2.3 Anti-inflammatory effects of ALOX15

Inflammation resolution is a precisely regulated process aimed at actively restoring tissue homeostasis (55). Its core lies in the fundamental transformation of cellular components and inflammatory mediator patterns within the inflammatory tissue (22). ALOX15 plays an indispensable role in this process, and its anti-inflammatory properties are realized through multiple synergistic mechanisms.

Firstly, studies have shown that ALOX15 is one of the key enzymes in the synthesis of specialized pro-resolving mediators (SPMs), including resolvins (RVs) and protectins D (PDs) (56–59). These mediators act as “stop signals” for the inflammatory response, which can reduce leukocyte migration (60), promote the apoptosis of pro-inflammatory neutrophils (61), induce the differentiation of highly efficient M2 macrophages (62), and inhibit T-cell migration and activation, thereby actively terminating inflammation and initiating tissue repair (63). For instance, in murine models of acute inflammation, the administration of RVs, particularly RvE1, significantly reduces the infiltration of neutrophils (64). In a mouse model of postoperative ileus, ALOX15 deficiency leads to decreased synthesis of PDs, resulting in increased neutrophil influx (65). And PD1 can block T-cell migration, reduce TNFα and interferon-γ secretion, and promote T-cell apoptosis (66). However, a balanced interpretation of these pro-resolving mechanisms requires caution and several lines of evidence challenge the notion that these mediators are key endogenous molecules for inflammation resolution. From a biosynthetic perspective, the classic SPM cascade has been questioned by in vitro enzymology studies, which indicate that many LXs and RVs are not efficiently produced from their precursors by human lipoxygenases, suggesting their in vivo generation may be very limited (67, 68). Furthermore, the identity and signaling of proposed G-protein-coupled SPM receptors have not been consistently validated in knockout mouse studies, and in humans, SPM levels have not been robustly linked to dietary precursor supplementation or consistently observed during the natural resolution phase of inflammation (69–71). More fundamentally, the accurate detection and quantification of SPMs in complex biological matrices presents a formidable analytical challenge. A hallmark of SPMs is that their reported concentrations are far lower than those of pro-inflammatory mediators, and reliable quantification is hampered by their instability and the limitations of current liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies (71). A recent critical evaluation argued that commonly used analytical approaches often fail to apply standard limit-of-detection (LOD) and limit-of-quantitation (LOQ) criteria, leading to the potential misidentification of background noise as genuine SPM signals and casting doubt on the very occurrence of many of these lipids in biological samples (72). These questions regarding the formation, signaling, and reliable quantification of SPMs collectively challenge their definitive role as primary endogenous mediators of resolution. Therefore, although exogenous SPMs or the modulation of ALOX15 activity show promising therapeutic potential, future research must urgently address the aforementioned controversies. In particular, efforts should focus on validating the endogenous functions of SPMs at physiologically relevant concentrations and delineating the specific contributions of SPM-dependent versus SPM-independent pathways in the pro-resolving actions of ALOX15.

Secondly, 13S-H(p)ODE, a major product of linoleic acid catalyzed by ALOX15, also exhibits anti-inflammatory activity (73), and can suppress inflammatory gene expression by activating peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway (74). Studies have shown that stimulating linoleic acid metabolism can induce the production of 13(S)-HODE in colonic epithelial cells. It can be subsequently converted by 13(S)-HODE dehydrogenase to 13-Oxo-ODE, which binds to PPARγ and reduces IL-8 secretion, thereby exerting an anti-inflammatory effect (75). In a cerebral ischemia model, 13(S)-HODE exerts neuroprotective effects by upregulating PPARγ protein levels, promoting its nuclear translocation and DNA binding to activate this pathway, consequently inhibiting the production of key pro-inflammatory mediators such as NF-κB, iNOS, and COX-2 (76). Beyond individual metabolites, ALOX15 generates a broader array of lipid mediators that act in concert. In a murine skin wound model, injury-induced ALOX15 expression in macrophages and stem cells produces monohydroxy oxylipins that collectively activate PPARγ. Alox15 deletion caused excessive collagen deposition, persistent pro-inflammatory gene expression (IL-6, IL-1β, Cxcl2, miR-21), and impaired PPARγ/adiponectin signaling, indicating loss of PPARγ’s anti-inflammatory brake on NLRP3 and TGF-β pathways. Reconstitution with a physiological oxylipin mixture restored normal healing and PPARγ activation, demonstrating that ALOX15-generated oxylipins synergistically suppress inflammation via PPARγ (77). Therefore, The ALOX15-PPARγ axis thus represents a critical node in inflammation resolution. Multiple ALOX15-derived oxylipins—including 13(S)-HODE and wound-induced monohydroxy lipids—serve as endogenous PPARγ ligands that cooperatively suppress NF-κB, promote alternative macrophage activation, and enhance tissue repair (74, 76, 77). This positions ALOX15 as a metabolic gatekeeper converting pro-inflammatory fatty acids into anti-inflammatory signals. Therapeutically, enhancing these endogenous ligands—rather than targeting ALOX15 directly—may offer a nuanced approach to resolving inflammation while preserving homeostatic functions.

Thirdly, ALOX15 itself serves as a canonical marker of alternative (M2) macrophage polarization in humans. In response to Th2 cytokines IL-4 or IL-13, human macrophages upregulate ALOX15 expression as part of a broader transcriptional program that promotes tissue repair and inflammation resolution (29, 78). This induction is mediated by STAT6 and can be further potentiated by efferocytosis through liver X receptor (LXR) activation, which integrates sterol metabolism with anti-inflammatory gene expression (78). Functionally, ALOX15 in M2 macrophages contributes to the biosynthesis of SPMs precursors such as 15-HETE and 17-HDHA, linking macrophage phenotype to the production of pro-resolving lipid signals. ALOX15 activity also influences cholesterol homeostasis and membrane remodeling, processes critical for effective efferocytosis and tissue repair (44). In the tumor microenvironment, ALOX15 signaling has been implicated in the polarization of tumor-associated macrophages (TAMs) toward an immunosuppressive M2-like phenotype, contributing to lymphoma progression (79). Conversely, in high-altitude hypoxic lung injury, downregulation of ALOX15 promotes M2 polarization and alleviates ferroptosis and inflammation (80). These findings underscore that the functional outcome of ALOX15 expression in macrophages is highly context-dependent. Understanding the regulatory networks that control ALOX15 expression and activity in specific disease settings will be essential for harnessing its therapeutic potential.

Furthermore, specific oxidized phospholipids generated via ALOX15 catalysis can inhibit the overactivation of innate immunity by blocking Toll-like receptor binding, thereby participating in the inflammation resolution program (81). Studies have found that when the concentration of oxidized phospholipids is 10-fold lower than that required to induce a pro-inflammatory response, they can potently suppress the upregulation of lipopolysaccharide-induced inflammatory cytokines (81). This demonstrates that some distinct effects of the same metabolites may be attributed to their varying concentrations.

Therefore, although ALOX15 exhibits pro-inflammatory activity during the early phase of inflammation, it plays a crucial anti-inflammatory and tissue-protective role during the resolution phase through multiple pathways, including the generation of pro-resolving mediators, activation of anti-inflammatory signaling pathways, and production of regulatory oxidized lipids. This underscores its complex yet pivotal dual role in the dynamic equilibrium of inflammation. The key metabolites and mechanisms involved in anti-inflammatory responses are summarized in Figure 2 and Table 2.

3 The pathophysiological role of ALOX15 in inflammation-related diseases3.1 Neuroinflammatory diseases3.1.1 Ischemic cerebrovascular disease

Numerous studies have demonstrated the role of ALOX15 in ischemic cerebrovascular disease (87, 88). Its involvement spans the entire disease process and exhibits an evolving “double-edged sword” characteristic over time. In the early phase of ischemia, increased release of AA and elevated intracellular calcium in the brain facilitate membrane binding and activation of ALOX15 (89). In a mouse model of transient middle cerebral artery occlusion, van Leyen et al. demonstrated that ALOX15 was significantly upregulated in the penumbra surrounding the core infarct, a brain region susceptible to ischemia-induced delayed cell death (87). At this stage, the mechanisms involve both direct neuronal injury and vascular disruption. As shown in the study by Zhang et al. (90), peroxynitrite triggers intracellular zinc release, which activates ALOX15, leading to ROS accumulation, p38 MAPK and caspase-3 activation, and ultimately causing mitochondrial dysfunction and neuronal death. In parallel, Jin et al. demonstrated that ALOX15 upregulation in endothelial cells results in degradation of the tight junction protein claudin-5, increased IgG extravasation, and exacerbate edema by compromising blood–brain barrier integrity (91). They are even associated with increased levels of the pro-apoptotic factor AIF, directly participating in cell death pathways within the ischemic area (92, 93).Conversely, functional inactivation of the ALOX15 gene protects mice from stroke (94), reduces blood-brain barrier leakage and edema formation (91), and also mitigates post-stroke behavioral deficits (95). Pretreatment of animals with ALOX15 inhibitors can replicate these protective effects. For instance, in a mouse model of transient middle cerebral artery occlusion, intraperitoneal administration of baicalein protects against ischemia-reperfusion injury by inhibiting ALOX15 pathway-mediated neuronal cell death (87). Which further confirms the early pro-injury role of ALOX15.

However, as the disease progresses into the subacute phase, a significant functional transformation occurs in ALOX15, with its derived mediators (including LXs and PDs) assume a pivotal role in neuroprotection and the promotion of inflammation resolution (22). For example, in rats with permanent middle cerebral artery occlusion, rosiglitazone not only induces the expression of LOX in the brain but also increases LXA4 levels while inhibiting the production of LTB4, thereby exerting neuroprotective effects (96). Additionally, in a rat model of ischemic stroke, activation of the LXA4 receptor effectively limits cortical inflammatory damage by inhibiting microglial activation and reducing neutrophil infiltration and recruitment, s