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Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review)

  • Authors:
    • Xiaorong Yang
    • Yongbo Tu
    • Na Liang
    • Lingli Li
    • Jian Zhang
    • Jingyu Xu
    • Chunming Li
  • View Affiliations / Copyright

    Affiliations: Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China, Department of Radiology, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China, Department of Pathology, The First Clinical Medical College of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China, Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China, Department of Cardiac Macrovascular Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China, The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou 563006, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 87
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    Published online on: August 20, 2025
       https://doi.org/10.3892/ijo.2025.5793
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Abstract

Lipoprotein‑associated phospholipase A2 (Lp‑PLA2), an important member of the phospholipase A2 superfamily, was originally investigated for its proinflammatory role in cardiovascular diseases. Recent studies have revealed its significant role in tumorigenesis: It can act as either a tumor promoter or a tumor suppressor depending on the context. The present review systematically outlined the dual mechanisms by which Lp‑PLA2 contributes to cancer pathogenesis. As a tumor promoter, it promotes cancer progression via the induction of epithelial‑mesenchymal transition, glutathione peroxidase 4‑mediated resistance to ferroptosis, and vascular endothelial growth factor‑­dependent angiogenesis; conversely, as a tumor suppressor, it inhibits tumor growth by suppressing the Wnt/β‑catenin pathway in breast cancer gene 1‑mutated cancers or by promoting apoptosis. Mechanistic investigations clarify the interactions between Lp‑PLA2 and critical oncogenic pathways, such as the Notch and HIF1α pathways, while emphasizing the functional dichotomy that is influenced by the microenvironment. Current evidence supports the development of microenvironment‑guided targeting strategies and the potential value of Lp‑PLA2 as a prognostic biomarker and therapeutic target. These findings contribute to a theoretical framework for comprehending the context‑dependent roles of Lp‑PLA2 and may guide the development of innovative therapeutic approaches.
View Figures

Figure 1

A brief illustration of the catalytic
active site of Lp-PLA2 and its catalytic mechanism. PLs typically
feature a saturated fatty acid at the sn-1 position of glycerol,
while the fatty acid at the sn-2 position may vary, being either
saturated, monounsaturated, or polyunsaturated. Notably,
polyunsaturated fatty acids at the sn-2 position are susceptible to
oxidation under conditions of oxidative stress, leading to the
formation of ox-PLs through a process referred to as lipid
peroxidation. Lp-PLA2 is a hydrolase enzyme characterized by a
catalytic triad active site (Ser273-Asp356-His376) that effectively
catalyzes the hydrolysis of the oxidized fatty acid at the sn-2
position, resulting in the release of ox-FFAs and lyso-PLs
(5). Lp-PLA2,
lipoprotein-associated phospholipase a2; PLs, Phospholipids,
ox-PLs, oxidized phospholipids, ox-FFAs, oxidized free fatty acids,
lyso-PLs, lysophospholipids.

Figure 2

Opposing roles of Lp-PLA2 in
different cancers: promoting or suppressing tumour progression. The
circular diagram presented illustrates the diverse roles of
Lp-PLA2, which is encoded by the PLA2G7 gene, in the process of
carcinogenesis. The diagram is segmented into various colored
sections that represent the oncogenic (red), anticarcinogenic
(black), and regulatory (indicated by arrows) functions of Lp-PLA2.
Each section provides detailed information regarding specific
cancer types, relevant cell lines (such as THP-1 for
PMA-differentiated macrophages and C666-1 for nasopharyngeal
carcinoma), as well as the molecular mechanisms or alterations in
gene expression that are modulated by Lp-PLA2. For example, in the
context of breast cancer, Lp-PLA2 influences tumorigenesis by
affecting the mutation status of BRCA1, whereas in hepatocellular
carcinoma, it plays a role in the regulation of STAT3/STAT1
signaling pathways. Additionally, the diagram indicates variations
in Lp-PLA2 expression levels (with upward arrows denoting increases
and downward arrows indicating decreases) and outcomes from
co-culture experiments (denoted by a plus sign). This visualization
emphasizes the intricate interactions of Lp-PLA2 within tumour
biology, highlighting its functional plasticity that is dependent
on the specific context of various TMEs. AKT, protein kinase B;
ALDH1A1, aldehyde dehydrogenase 1 family member A1; BRCA1, breast
cancer gene 1; CD8, cluster of differentiation 8; ERK1/2,
extracellular signal-regulated kinases 1 and 2; GPX4, glutathione
peroxidase 4; HDAC3, histone deacetylase 3; HIF-1α,
hypoxia-inducible factor-1 alpha; ICAM-1, intercellular adhesion
molecule-1; IL-1β, interleukin-1 beta; IL-6, interleukin-6; JAK,
Janus kinase; LPC, lysophosphatidylcholine; LP,
lysophospholipid/lipid peroxidation; Lp-PLA2,
lipoprotein-associated phospholipase a2; .MCP-1, monocyte
chemoattractant protein-1; MMP-9, matrix metalloproteinase-9;
mTORC1, mechanistic target of rapamycin complex 1; oxFFA, oxidized
free fatty acid; PAF, platelet-activating factor; PAF-AH,
platelet-activating factor acetylhydrolase; PI3K, phosphoinositide
3-kinase; PLA2G7, phospholipase A2 group VII; PGE2, prostaglandin
E2; STAT, signal transducer and activator of transcription; THP-1,
human monocytic leukemia cell line; TNF-α, tumor necrosis
factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VEGF,
vascular endothelial growth factor; Wnt/β-catenin, wingless-type
MMTV integration site family/β-catenin signaling pathway.

Figure 3

The role of Lp-PLA2 in lipid
metabolic reprogramming and the associated downstream signaling
pathways in cancer. Lp-PLA2 is notably upregulated in cancer. Its
enzymatic product, LPC, serves dual oncogenic roles: i)
Facilitating the assembly of lipid rafts to improve membrane
fluidity and (ii) activating Gαi-ERK1/2 signaling through the
LPC-GPCR pathway. Additionally, metabolites of AA derived from
Lp-PLA2 contribute to tumor progression through two interrelated
pathways: the established COX-2/PGE2 signaling cascade and the
recently discovered 12-HETE-PPARγ pathway. Collectively, these
mechanisms play a significant role in driving cancer pathogenesis.
AA, arachidonic acid; ACC, acetyl-CoA carboxylase; AKT, protein
kinase B; cAMP, cyclic adenosine monophosphate; CDK4,
cyclin-dependent kinase 4; COX-2, cyclooxygenase-2; EP2,
prostaglandin E2 receptor 2; ERK1/2, extracellular signal-regulated
kinases 1 and 2; FASN, fatty acid synthase; GBY, G-protein βγ
subunit; Gai, inhibitory G-protein α subunit; GPCR,
G-protein-coupled receptor; 12-HETE-PPARγ,
12-hydroxyeicosatetraenoic acid-peroxisome proliferator-activated
receptor γ; 12-LOX, 12-lipoxygenase; LPC, lysophosphati-dylcholine;
Lp-PLA2, lipoprotein-associated phospholipase a2; mTOR, Mechanistic
target of rapamycin; PC, phosphatidylcholine; PI3K,
phosphoinositide 3-kinase; PIP3,
phosphatidylinositol-trisphosphate; PKA, protein kinase A; PPARγ,
peroxisome proliferator-activated receptor γ; PGE2, prostaglandin
E2; PTGER2, prostaglandin E2 receptor 2; Rac1, Ras-related C3
botulinum toxin substrate 1; RhoA, Ras homolog family member A;
VEGF, vascular endothelial growth factor.

Figure 4

Lp-PLA2-Driven immunosuppression in
the TME. PLA2G7 orchestrates tumor immune evasion through two
integrated mechanisms: (i) cell-intrinsic suppression of T
lymphocyte proliferation to cripple antitumor immunity, and (ii)
cell-extrinsic polarization of macrophages toward the M2 phenotype
that establishes an immunosuppressive niche. These coordinated
actions culminate in adverse clinical outcomes and acquired
immunotherapy resistance. CD8, cluster of differentiation 8; CXCL9,
C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine
ligand 10; HNF-κB, nuclear factor kappa-light-chain-enhancer of
activated B cells; IL-10, interleukin-10; Lp-PLA2,
lipoprotein-associated phospholipase a2; PD-L1, programmed
death-ligand 1; PLA2G7, phospholipase A2 group VII; STAT1, signal
transducer and activator of transcription 1; STAT3, signal
transducer and activator of transcription 3; TGF-β, transforming
growth factor β; TME, tumor microenvironment.

Figure 5

Therapeutic strategies targeting
Lp-PLA2 in tumor treatment. (A) Therapeutic strategies aimed at
targeting Lp-PLA2 in the context of tumour treatment. Three
distinct methodologies are presented: i) The small-molecule
inhibitor darapladib, which enhances lipid metabolism, thereby
increasing the susceptibility of cancer cells to ferroptosis. ii)
Monoclonal antibodies (1H8 IgG and 1Ag VH-Fc) that selectively bind
to specific epitopes of Lp-PLA2, effectively inhibiting the
proliferation and migration of tumor cells. B and C the synergistic
antitumor effects observed when darapladib is combined with PD-1
blockade. In vitro and in vivo studies both indicate
that the combination of darapladib with a PD-1 inhibitor results in
a significant reduction in tumor growth compared to the effects of
monotherapy. AA, arachidonic acid; CCL5, C-C motif chemokine ligand
5; CD8, cluster of differentiation 8; CXCL10, C-X-C motif chemokine
ligand 10; FFA, free fatty acid; IL-1β, interleukin-1 β; LPC,
lysophosphatidylcholine; Lp-PLA2, lipoprotein-associated
phospholipase a2; Lyso-PE, lysophosphatidylethanolamine; MAPK,
mitogen-activated protein kinase; NF-κB, nuclear factor
κ-light-chain-enhancer of activated B cells; Ox-PE, oxidized
phosphatidylethanolamine; PD-1, programmed cell death protein 1;
PEP, phosphatidylethanolamine plasmalogen; PI3K-AKT,
phosphoinositide 3-kinase-protein kinase B pathway; TAMs,
tumour-associated macrophages; TNF-α, tumor necrosis factor-α.
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Copy and paste a formatted citation
Spandidos Publications style
Yang X, Tu Y, Liang N, Li L, Zhang J, Xu J and Li C: Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review). Int J Oncol 67: 87, 2025.
APA
Yang, X., Tu, Y., Liang, N., Li, L., Zhang, J., Xu, J., & Li, C. (2025). Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review). International Journal of Oncology, 67, 87. https://doi.org/10.3892/ijo.2025.5793
MLA
Yang, X., Tu, Y., Liang, N., Li, L., Zhang, J., Xu, J., Li, C."Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review)". International Journal of Oncology 67.5 (2025): 87.
Chicago
Yang, X., Tu, Y., Liang, N., Li, L., Zhang, J., Xu, J., Li, C."Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review)". International Journal of Oncology 67, no. 5 (2025): 87. https://doi.org/10.3892/ijo.2025.5793
Copy and paste a formatted citation
x
Spandidos Publications style
Yang X, Tu Y, Liang N, Li L, Zhang J, Xu J and Li C: Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review). Int J Oncol 67: 87, 2025.
APA
Yang, X., Tu, Y., Liang, N., Li, L., Zhang, J., Xu, J., & Li, C. (2025). Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review). International Journal of Oncology, 67, 87. https://doi.org/10.3892/ijo.2025.5793
MLA
Yang, X., Tu, Y., Liang, N., Li, L., Zhang, J., Xu, J., Li, C."Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review)". International Journal of Oncology 67.5 (2025): 87.
Chicago
Yang, X., Tu, Y., Liang, N., Li, L., Zhang, J., Xu, J., Li, C."Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review)". International Journal of Oncology 67, no. 5 (2025): 87. https://doi.org/10.3892/ijo.2025.5793
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