The COX enzyme is the initial catalyst in the arachidonic acid pathway for prostaglandin (PG) and thromboxane (Tx) synthesis, existing in three isomeric forms: COX-1, COX-2, and COX-3 (19). Both COX-1 and COX-2 enzymes facilitate the conversion of cell membrane phospholipids to arachidonic acid via phospholipase A2, followed by its conversion to PGH2 through PGG2 (20)( Figure 2 ).COX-1 is a constitutive enzyme essential for normal physiological functions and widely distributed across various tissues to safeguard cellular integrity (21). There is no significant difference in the expression level of COX-1 between tumor tissues and normal tissues (22).

COX-2 is an inducible enzyme that performs a crucial function in the pathophysiological process of various cancers, including pancreatic, breast, prostate, lung, liver, cervical, bowel, and skin cancer (23–28). It is either not expressed or expressed at low levels in most normal tissues. The expression of COX-2 is associated with inflammation, cell survival, proliferation, angiogenesis, invasion, and metastasis. In response to growth factors and endotoxins, COX-2 is briefly but strongly expressed. The overexpression of COX-2 significantly enhances the production of PGE2, leading to increased cell aggressiveness (29). PGE2 contributes to the development and progression of many cancers by activating the membrane receptors EP (including EP1, EP2, EP3, and EP4 receptors) and the nuclear receptor PPARδ of target cells (30). Other studies have indicated that high expression of COX-2 can hinder the apoptosis of tumor cells, which is crucial in the early stages of tumor formation (31). The overexpression of COX-2 can result in increased synthesis of PG, which plays a significant biological role in tumor growth and proliferation. PGE2 can impede apoptosis induced by selective COX-2 inhibitors by upregulating the anti-apoptotic protein bc-l2 (32). Kajita et al. discovered that the level of specific enzymes in the PG synthesis pathway, such as TXA2 synthetase, increased in papillary thyroid carcinoma. Additionally, the expression of COX-2 protein in papillary thyroid carcinoma was higher than in normal thyroid tissue and varied greatly, indicating that COX-2 could promote the growth of the thyroid papillary gland (33). These findings suggest that the increased expression of these enzymes may contribute to the pathogenesis of tumors.

What’s more, angiogenesis is the physiological basis of solid cancer growth and metastasis (34). The high expression of COX-2 and its metabolite PGE2 promotes angiogenesis by up-regulating angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (35). COX-2 also promotes the metastasis and invasion of ovarian cancer by inducing matrix metalloproteinases (MMPs) in the extracellular matrix and the decomposition of collagen matrix, which may be involved in the activation of the PI3K/AKT signaling pathway (36–38). Inhibition of COX-2 with its specific inhibitor NS-398 can increase the expression of E-cadherin and inhibit the expression of slug, vimentin, MMP2, and MMP9, thereby suppressing the invasion and metastasis of ovarian cancer cells under estrogen treatment (39–41). Moreover, overexpression of COX-2 in ovarian cancer cells can directly up-regulate Bcl-2 expression through the increased synthesis of PGs. In addition, COX-2 can inhibit the proliferation of T and B lymphocytes through its product PGE2, and also inhibit the synthesis of cytokines to reduce the cytotoxicity of natural killer cells (42). Therefore, the role of COX-2 and PGE2 in promoting tumor proliferation and invasion, reducing tumor cell apoptosis, and promoting tumor angiogenesis has been confirmed, and it proved that they play an important role in carcinogenesis, and have the function of promoting tumor by inhibiting the body’s immunity (43).

LOX is the initial enzyme in the leukotriene (LT) pathway of arachidonic acid. Isoenzymes of LOX consist of 5-LOX, 12-LOX, and two isomers of 15-LOX (15-LOX-1, 15-LOX-2). However, 5-LOX, 12-LOX, and 15-LOX-1 have pro-tumor effects, while 15-LOX-2 appears to have anticancer effects (44).

LOX catalyzes the oxidation of arachidonic acid to 5-HPETE, which is subsequently metabolized to 5-HETE (5-hydroxyeicosatetraenoic acid) and LTB4 (leukotriene B4) (45). As a member of the arachidonic acid oxygenase family, 5-LOX is composed of 674 amino acids and is a monomeric enzyme containing iron ions. 5-LOX can be transcriptionally regulated by transcription factor Er, Sp1, nuclear factor-κB (NF-κB), and GATA (46). 5-LOX is activated by 5-LOX activating protein (FLAP) to catalyze arachidonic acid, which is released from the phospholipid bilayer by phospholipase A2 (47). Arachidonic acid is transformed into 5-HPETE, which can be metabolized by glutathione peroxidase into 5-HETE (48). The activity of 5-LOX leads to the formation of unstable LTA4, which can be converted to LTB4, LTC4,LTD4 and LTE4 (49). More significantly, the average endogenous level of LOX metabolites such as 12-HETE (12-hydroxyeicosatetraenoic acid) in primary prostate cancer were found to be significantly higher than that in non-neoplastic prostate tissue. It is suggested that 12-HETE is crucial in the progression of prostate cancer and the LOX pathway may be a target for the treatment and prevention of prostate cancer (50). 12-HETE has also been shown to play an important role in cancer adhesion, invasion, and metastasis. It stimulates NF-κB activation and NF-κB-dependent ICAM-1 expression through RhoA and PKCα signaling pathways, and the Rho/Rac family of GTases also play a role in cell adhesion and migration. 12-HETE can also promote the secretion of protease and enhance the motor capacity of tumor cells (51)( Figure 3 ).

Various environmental and chemical carcinogens activate pro-tumor mediators during carcinogenesis, including 5-LOX, whose metabolite 5S-HERE acts as a substrate for COX-2 to form bicyclic and is further transformed into two pro-angiogenic mediators (52). However, the specific role of these products in cancer development needs better understanding, given the pro-angiogenic role of these enzymes. As a result, 5-LOX is considered a new target for cancer prevention and treatment, while LETA4 hydrolase is considered a tumor promoter whose inhibitors can reduce tumor growth and development (53). Although most of the metabolites synthesized by the COX and LOX pathways can promote tumorigenesis. Additionally, CYP450 monooxygenase-derived metabolites can also regulate the occurrence and growth of cancer, playing both a pro-tumor and anti-tumor role (54).

Cytochrome P450 (CYP) belongs to the group of hemoglobin enzymes. It is a super-family gene encoding isoenzymes with a structure and function related to CYP. The combination of reduced CYP and carbon monoxide (CO) has a special light absorption peak at 450 nm (55). The expression of CYP surface oxidase is significantly high in cancer tissues, while almost no expression is found in adjacent normal tissues. This confirms that CYP surface oxidase and its metabolites can regulate the occurrence and growth of cancer, playing both a pro-tumor and anti-tumor role. It has been shown that reducing the expression and activity of CYP450 has anti-tumor effects, making it a promising anti-cancer treatment method (56) ( Figure 4 ).

Arachidonic acid produces epoxyeicosatrienoic acid (EETs) and hydroxyeicosatetraenoic acid (HETEs) through the catalysis of cytochrome P450 surface oxidase. EETs are further categorized into four types: 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET (57, 58). Recent studies have focused on the role and mechanism of EETs in important biological processes of tumors, including proliferation, apoptosis, and metastasis (59). These studies have revealed that EETs can significantly enhance the proliferation of tumor cells and protect them from TNF-α-induced apoptosis by up-regulating anti-apoptotic proteins Bcl-2 and Bcl-XL, while down-regulating pro-apoptotic proteins Bax and Bak, thereby reducing the activity of caspase-3 protein (60).

In light of the characteristics of the CYP gene superfamily, research on the correlation between CYP and gynecologic tumors primarily focuses on specific CYP polymorphisms involved in sterol hormone metabolism. The polymorphisms of CYPlAl, CYPlBl, CYPl7, and CYPl9 have garnered increasing attention in relation to gynecologic tumors (61, 62). CYPlAl is an enzyme involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs), which are significant metabolically active chemical carcinogens, and is expressed in various sterol hormone-reactive tissues such as the ovary, mammary gland, and prostate. Studies have shown that the CYPlAl Ile/Val and Val/Val genotypes are significantly more common in patients with epithelial ovarian tumors, indicating that women with these genotypes are at higher risk for ovarian cancer (63). CYP and its lipid metabolites play a role in the development of ovarian tumors, and their expression may be a crucial marker for tumor development (64).

AA catalyzes the synthesis of prostaglandins (PGs) and thromboxanes (TXs) through cyclooxygenase (COX). There are two subtypes of COX: COX-1 and COX-2. COX-1 is widely distributed in tissues, with no significant difference in expression levels between tumor tissues and normal tissues. On the other hand, COX-2 is closely associated with the development of inflammation and tumors. Overexpression of COX-2 significantly promotes the biosynthesis of prostaglandin E2 (PGE2). PGE2 stimulates the occurrence and progression of various cancers by activating membrane receptors EP and nuclear receptor PPARδ in target cells.

Recently, Mauricio A. Cuello discussed the impact of COX-2 on the immune spectrum of high-grade serous ovarian cancer (HGSOC). Elevated levels of COX-2 may hinder NK cell activity, promote the expression of cytotoxic T lymphocyte-associated protein-4 (CTLA-4), affecting the efficacy of anti-CTLA-4 immunotherapy in HGSOC patients. Targeting COX-2 before anti-CTLA-4 immunotherapy could be a promising strategy to enhance the effectiveness of immunotherapy in ovarian cancer patients (42). Additionally, Ning Ding’s research found that the overexpression of COX-2 in SKOV3 cells (human ovarian cancer cells) is associated with the acquisition of stem cell properties, inflammatory microenvironment, enhanced tumor sphere formation, increased cell proliferation, and enhanced metastatic potential, all contributing to ovarian cancer progression and metastasis (65). Based on current research, the roles of COX- and LOX-derived class of diterpenes in cancer have been fairly well studied. COX-1, COX-2, mPGES-1, EP1, and EP2 are mainly expressed in epithelial cells of human epithelial ovarian cancer (66). The expression of COX-2 in ovarian cancer cells is regulated by various cytokines, such as EGF, vitamin D, IL-1β, which can stimulate the proliferation, migration, and angiogenesis of ovarian cancer cells. It mainly enhances the proliferation and migration of human ovarian cancer CAOV-3 cells by activating the phosphatidylinositol 3 kinase/protein kinase B (PI3-k/Akt) pathway (67). Moreover, by analyzing epithelial ovarian cancer tissues and cell lines, COX-2 also regulates cell growth and apoptosis through the PI3K/AKT signaling pathway in ovarian cancer tissues (68).

In the Lipoxygenase (LOX) pathway, AA is catalyzed by the LOX enzyme, undergoing an oxidation reaction at specific sites to form hydroxyl-containing products, namely Hydroxyeicosatetraenoic acid (HETEs, including 5-, 8-, 12-HETE, etc.). Additionally, there are lipoxins (LXs), leukotrienes (LTs), and other products, which will not be the focus here.

Research in ovarian cancer has found an increased expression level of 5-LOX in the immune stroma of tissues, suggesting a specific impact on the tumor microenvironment during tumor initiation and progression (47). Under hypoxic conditions, the transcription levels of 5-LOX and ALOX5AP in ovarian cancer cell lines also increase, significantly correlating with poor overall survival, progression-free survival, lymphatic infiltration after initial treatment, rapid relapse, and other adverse clinical pathological features. Current studies have discovered that various LOX pathway metabolites, such as HETEs, play a role in inhibiting tumor cell apoptosis, stimulating angiogenesis, enhancing cell proliferation, and promoting metastasis. The presence of 12-HETE has been identified in high-grade serous ovarian cancer and normal ovarian epithelial tissues. The 12-LOX - 12-HETE system is present in two epithelial ovarian cancer cell lines, OVCAR-3 and SK-OV-3, with high levels of 12-LOX mRNA and protein (69, 70). Exposure to arachidonic acid increases the production of 12-HETE in both epithelial ovarian cancer cell lines. Numerous studies have confirmed its ability to promote the proliferation, adhesion, migration, and angiogenesis of various cancer cells such as breast, prostate, and colon cancer. These findings collectively indicate that metabolites produced by the LOX pathway can play a role in the development of ovarian cancer through different isoenzymes (71).

Most studies on gynecologic malignant tumors have focused on the arachidonic acid oxygenase pathway, particularly examining the roles of PGE2 and PGF2a along with their respective receptors. While some research has touched upon the P450 cytochrome epoxygenase pathway in ovarian cancer, there is a lack of in-depth mechanistic studies in this area (72). Research indicates that CYP2C8 and CYP3A5 are prominently expressed in the majority of ovarian tumors, showing higher IHC staining intensity of CYP3A5 and other CYP enzymes in primary ovarian cancer tissues. In contrast, CYP3A4 is expressed at significantly lower levels in ovarian cancer (73, 74).

Arachidonic acid is converted into four eicosanoids (EETs) by cytochrome P450 oxygenases (CYP oxygenases). Human EETs are synthesized by the CYP2 family, including the CYP2C and CYP2J families. EETs are intermediate products downstream of the VEGF signaling pathway, regulating vascular tone and maintaining vascular homeostasis. They have been shown to promote endothelial cell proliferation, enhance endothelial cell migration through pathways such as eNOS, MEK/MAPK, and PI3K, and boost VEGF-mediated angiogenesis. Angiogenesis plays a crucial role in tumor development, enabling tumors to access more nutrients and oxygen for continued growth, spread, and metastasis by providing pathways for tumor cells to travel through the bloodstream to distant sites.