Patients suffering from EC have higher serum concentrations of TC, LDL-C and TG than control subjects (Lindemann et al., 2009; Melvin et al., 2012; Ghahremanfard et al., 2015). In contrast, a reduction in serum HDL-C levels was found in EC patients (Table 1). Because EC is strongly linked to obesity and hyperinsulinemia, dyslipidemia in EC cohorts may reflect host metabolic risk (and shared endocrine/inflammatory mechanisms) rather than tumor-specific lipid effects, especially when BMI and diabetes/insulin and lipid-lowering therapy are not rigorously controlled. In a large prospective cohort study, a positive correlation between serum TG levels and EC risk was observed, but no significant association was found between serum LDL-C and HDL-C with EC risk (Seth et al., 2012). Essentially similar results have been reported by other authors (Lindemann et al., 2009). Since high serum cholesterol levels promote chronic inflammation, estrogen imbalance (Yang and Wang, 2019; Lin et al., 2021), and TG and cholesterol esters serve as reservoir of lipids for cancer (Butler et al., 2020), these lipid patterns are mechanistically compatible with EC-promoting endocrine–inflammatory milieus; however, causality cannot be inferred from observational associations and reverse causation (tumor- or preclinical disease–driven lipid changes) remains possible. By contrast, one study indicated that patients over 55 years of age with low TC and LDL-C levels had a higher risk of EC (Swanson et al., 1994). Such directionally discordant findings underscore potential confounding by nutritional status, comorbidities, and medication use, and argue for longitudinal, well-phenotyped cohorts. One of the lipids strongly associated with EC is 27-Hydroxycholesterol (27-OHC). 27-OHC is formed in EC tissues and acts as an agonist for the Liver X receptor (LXR), promoting the proliferation of EC epithelial cell (Gibson et al., 2018). Notably, this evidence is primarily tissue-based and does not establish 27-OHC as a validated circulating biomarker for EC. Beyond cholesterol itself, lipoproteins such as HDL-C and LDL-C may also act as carriers of microRNAs and inflammatory mediators, influencing tumor–stroma interactions and systemic cancer biology (Vickers et al., 2011).

Similar to EC patients with CC have higher serum concentrations of TC, LDL-C and TG than control subjects (Lindemann et al., 2009; Melvin et al., 2012; Ghahremanfard et al., 2015), whereas reduced serum HDL-C levels (Table 1). In a retrospective study of early-stage CC patients, increased serum TC and TG levels were associated with worse overall survival (Lin et al., 2021; Jiang et al., 2022). In addition, serum TC and LDL-C levels in CC patients were positively associated with disease progression (Raju et al., 2014). It was suggested that maintaining physiological concentrations of TG and TC in serum may have an impact on overall survival of CC patients (Lin et al., 2021). By contrast, one study showed that fifty years old or older patients with CC who have an elevated serum TG level have a higher survival rate than patients with a lower serum TG level (Jiang et al., 2022). This association was not observed in patients younger than 50 years old (Jiang et al., 2022).

In OC patients, the available data on serum TC, LDL-C and TG are heterogeneous. Some data indicate increased, others decreased serum/plasma concentrations of these lipids (Table 1). However, serum HDL-C concentrations were lower in OC patients compared to controls, similar to EC and CC patients. Melvin et al. found that serum levels of TC, TG, ApoB/ApoA ratio and LDL-C/HDL-C ratio were higher in OC patients compared with the control group (Melvin et al., 2012). Some authors reported the association of high TG with reduced survival in patients with OC (Ghahremanfard et al., 2015). The lower HDL-C/LDL-C ratio was also associated with a more advanced stage of epithelial ovarian cancer (EOC) (according to the International Federation of Gynecology and Obstetrics classification - FІGО) (Lemieux et al., 2001), and a lower serum HDL-C/TC ratio in EOC was linked to a tendency toward chemoresistance (Lemieux et al., 2001). Importantly, OC cohorts are particularly heterogeneous (histology, stage, treatment exposure, inflammatory burden/ascites, and cachexia), which can drive “directionally discordant” lipid findings and increase the likelihood of reverse causation (tumor-driven lipid changes rather than lipid-driven tumor risk). Overexpression of the LDL receptor (which plays a key role in cholesterol transport into cells) in patients with EOC undergoing platinum therapy is associated with a poor prognosis (Huang et al., 2021). These findings suggest that the transport of cholesterol into cells and possibly its metabolism to oxysterols and/or estrogens may be involved in drug resistance in EOC (Huang et al., 2021).

Published data suggest that changes in serum lipid profile depend on the type of GCs, disease progression and treatment outcomes (Bel’skaya et al., 2019; Onwuka et al., 2020; Faur et al., 2022). The most repeatable changes in serum lipid profile observed in patients with GCs relate to decreased HDL-C. This finding is also consistent with obesity-associated dyslipidemia (increased TG and decreased HDL-C), which is a major risk factor for GCs (Reeves et al., 2007). Decreased serum HDL-C concentration accompanied by increased concentrations of TC, LDL-C and TG (Table 1) leads to an increase in TC/HDL-C, LDL-C/HDL-C and TG/HDL-C ratios, which are generally considered indicators of a higher risk of cardiovascular disease (Seth et al., 2012). It is also generally accepted that an elevated serum TG/HDL-C ratio indicates a higher risk of metabolic syndrome (Qahremani et al., 2023). However, these ratios should be interpreted cautiously in oncology because cachexia/nutritional status, systemic inflammation, and treatment-related lipid shifts can strongly influence circulating lipids and may confound prognostic associations. Recent studies highlight the prognostic potential of non-HDL cholesterol (non-HDL = TC - HDL-C), which may be more strongly associated with cancer risk than individual lipid parameters (Fang et al., 2024). It can therefore be concluded that patients with cardiovascular disease and/or metabolic syndrome are potentially more susceptible to GCs. Furthermore, it has been postulated that higher HDL-C has anti-inflammatory and antioxidant properties including promotion of cholesterol efflux and reverse cholesterol transport (Raju et al., 2014). Therefore, it can be hypothesized that a significant decrease in serum HDL-C could promote the development of chronic inflammation and oxidative stress in GC patients. The data presented so far suggest that oxidative stress, chronic inflammation and cancer are closely linked (Neganova et al., 2021). Recently published results based on a large and long-term study of multiple cancer types, including GCs, show that a decrease in serum HDL-C levels was associated with a higher risk of death (Yang and Wang, 2019). An association between serum LDL-C and metastasis has also been reported (Ghahremanfard et al., 2015; Sun et al., 2016). In addition, serum lipid profiles of patients with GCs showed higher TG and apolipoprotein A (apoA) levels, but lower HDL-C, LDL-C and TC levels compared to benign ovarian tumors, endometriosis and uterine leiomyomas (Sun et al., 2016).

Оverall, the associations betwen blood lipid profiles in GCs patients (similar to other human cancers) are very complex, cancer type specific and not fully elucidated. The results of several studies are contradictory, but preliminary conclusions can be drawn: Patients suffering from EC and CC have increased serum TC, TG and LDL-C concentrations and decreased serum HDL-C concentrations. OC patients are characterized by decreased serum and HDL-C levels, while the changes in serum TC, TG and LDL-C concentrations are inconsistent. Currently, however, serum lipids are not incorporated into routine GC diagnosis or treatment decisions. Moreover, longitudinal data suggest that systemic lipid levels can change during chemotherapy or radiotherapy, potentially serving as predictors of treatment response (Tian et al., 2019). However, it is not excluded that the availability of new, more sophisticated diagnostic techniques, including GC-MS, LC-MS, and electrospray ionization mass spectrometry (ESI-MS), will allow the inclusion of a more extensive serum lipid profile (e.g., including fatty acids (FAs) and/or specific complex lipids such as phospholipids, sphingolipds etc.) in the diagnosis and treatment efficacy of some GCs in the near future. Therefore, further studies are needed to clarify the changes in serum lipid profile in GC patients and the impact of abnormal blood lipids on the development and treatment of GC.

In EC cohorts, lower circulating SFAs have been reported (Gaudet et al., 2012; Audet-Delage et al., 2018). The major n-6 PUFA linoleic acid (LA, 18:2) was decreased in serum in both a large population-based study and a smaller preoperative postmenopausal cohort (Gaudet et al., 2012; Audet-Delage et al., 2018).

Analysis of FA in red blood cells (RBCs) revealed that the total amount of SFA and the DPA were higher in CC and OC patients compared to controls, while linoleic acid (LA, 18:2 n-6) and DHA were significantly lower (Bannikoppa et al., 2017). Because RBCs lipids represent FA status over ∼120 days, they provide a “long-term metabolic fingerprint” of the host, that can be potentially useful for longitudinal monitoring (Fenton et al., 2016). This is particularly important because RBC phospholipid PUFA composition correlates with systemic organ PUFA levels (Lai et al., 2025), making it a robust biomarker for whole-body lipid status and potentially a better indicator of chronic metabolic shifts during cancer progression or treatment. At the same time, RBC FA patterns remain sensitive to background diet, obesity/insulin resistance, and inflammatory state, so case-control differences should be interpreted with attention to match/adjust for these factors and to standardize sample handling. Several studies report significant alterations in the serum FA profile of patients with EOC. The level of esterified SFA (lauric acid – 12:0, palmitic acid – 16:0, stearic acid – 18:0) was higher in the serum of patients with EOC than in control subjects (Yin et al., 2016). In contrast, esterified n-6 PUFA (GLA - gamma-linolenic acid, γ18:3 n-6, and ARA–arachidonic acid, 20:4 n-6) and n-3 PUFA (EPA - eicosapentaenoic acid, 20:5 n-3; and DHA-docosahexaenoic acid, 22:6 n-3) were lower in EOC patients than in healthy controls (Yin et al., 2016). This pattern results in an increased SFA/PUFA ratio, which Yin et al. (Yin et al., 2016) proposed as a potential biomarker to diagnose patients with EОC. However, other studies have reported that 12:0 and 18:0 were higher in the serum of EOC patients compared to healthy controls, but myristic acid (14:0) and 16:0 were lower, which highlights a controversy likely due to patient heterogeneity, dietary intake, menopausal status, tumor stage, and different lipidomics platforms (Bannikoppa et al., 2017). Recent studies also demonstrate that FA profile of membrane phospholipids, not just total serum FA, is a major determinant of cancer cell phenotype. Elevated MUFA/SFA ratios, driven by increased stearoyl-CoA desaturase-1 (SCD1) activity, confer resistance to ferroptosis, whereas SCD1 inhibition reduces MUFA levels, increases PUFA incorporation, and restores susceptibility to lipid peroxidation and ferroptosis inducers (Varynskyi and Schick, 2024). This finding is clinically relevant because it connects FA desaturation indices (16:1/16:0, 18:1/18:0) with therapeutic vulnerabilities, suggesting they may serve as functional biomarkers of lipid metabolic reprogramming. The concentrations of monounsaturated FAs (MUFA) (palmitoleic acid, 16:1), n-6 PUFA (GLA, 20:2 n-6, and adrenic acid 22:4 n-6) and n-3 PUFA (DPA - docosapentaenoic acid, 22:5 n-3, ALA - α-linolenic acid, 18:3 n-3, EPA and DHA) in the serum of EOC patients were lower than in control subjects (Yin et al., 2016). Taking the data presented above together, it can be concluded that the ratio of some esterified SFA/esterified PUFA and the levels of some SFA, MUFA, n-3 and n-6 PUFA may be useful potential biomarkers to diagnose patients with EOC. Together, these findings support the idea that combined FA ratios (SFA/PUFA, MUFA/SFA) and desaturation indices (16:1/16:0, 18:1/18:0) may serve as integrated biomarkers of EOC lipid metabolism. Still, standardization of lipidomic methods, stratification by histological subtype (e.g., high-grade serous vs. clear-cell EOC), and adjustment for metabolic comorbidities are urgently needed before clinical implementation (Zhao et al., 2022). Moreover, metabolomic studies have demonstrated that serum FFA signatures can differentiate EOC from benign ovarian disease and were successfully used to build early-stage EOC diagnostic models (Katoh et al., 2023). Importantly, tumor SCD1 expression correlates with circulating monounsaturated FFA patterns, suggesting that systemic lipid alterations reflect tumor-intrinsic metabolic reprogramming (Katoh et al., 2023).

Table 2 presents available data on serum or red blood cells FA levels in patients with GC.

Overall, circulating FA profile alterations in GCs are heterogeneous, partly contradictory, and influenced by multiple factors including tumor subtype, host metabolism, and methodology. While preliminary evidence supports the use of FA ratios and desaturation indices as potential biomarkers, their clinical translation requires (i) standardized lipidomics protocols, (ii) larger longitudinal studies stratified by tumor type, and (iii) correlation with treatment outcomes and immune-metabolic markers.

The effect of ARA and DHA on cell proliferation were investigated in several EC cell lines and in animal models (Tessier-Prigent et al., 1999; Zheng et al., 2014). Іt has been shown that DHA inhibits in a dose-dependent manner cell proliferation both in vitro and in vivo and promotes apoptosis by inhibiting mTOR signaling pathways (Zheng et al., 2014; Lubes and Goodarzi, 2018). In contrast, ARA stimulated cell proliferation both in vitro and in vivo (Butler et al., 2020). Moreover, treatment with DHA resulted in a rapid and dose-dependent suppression of phosphorylation of S6 (ribosomal protein - a key downstream component of the akt/mTOR signaling pathway that plays an important role in cancer cell survival) and phosphorylation of Akt (Zheng et al., 2014). Overall, these results suggest that ARA and DHA may play opposing regulatory roles in cell signaling pathways in EC (Zheng et al., 2014; Butler et al., 2020; West et al., 2020). These effects are consistent with reports showing that DHA can modulate membrane lipid rafts, enhance oxidative stress, and trigger ferroptosis-like cell death under certain conditions.

It has been shown that treatment of HeLa CC cells with 18:1 increased proliferative capacity, cell migration, and invasion ability (Yang et al., 2018). Because most CC evidence comes from HPV + cell lines, translation to patient tumors may depend on viral oncogene context, baseline metabolic state, and whether MUFA exposure reflects diet versus tumor-driven SCD1 activity. Іncreased MUFA content in the plasma membrane protects cancer cells from the cytoxic effects of SFA thus promoting cancer cell survival (Tesfay et al., 2019). In turn, GLA, EPA, ALA and DHA were found to accelerate the uptake of vincristine by HeLa CC cells and thus increase the therapeutic effect (Das et al., 1998). These “chemosensitization” findings are hypothesis-generating; they require confirmation in contemporary CC models and with clinically used regimens, because drug transport and membrane effects are highly assay- and dose-dependent.

It has been suggested that 18:1, the major MUFA in the human body, stimulates cell proliferation by activating Akt (also known as protein kinase B- PKB), whereas 16:0, the most abundant SFA, next to 18:0 in the human body, triggers apoptotic cell death and inhibits Akt pathway in several OC cell lines in a dose-dependent manner (Uddin et al., 2017). Blocking the FFA receptor 1 (FFAR1) in OC cell lines has been shown to reverse the proliferative effects of 18:1, while 16:0 inhibits pro-oncogenic signaling via the Akt pathway, highlighting the role of specific FAs in influencing cancer cell behavior (Uddin et al., 2017). In human ovarian granulosa tumor cells n-3 PUFA significantly reduces cancer cell viability and proliferation (Zheng et al., 2014; Yao et al., 2022). Moreover, the treatment by n-3 PUFAs increases the number of apoptotic cells (Yao et al., 2022). Another study has shown that DHA slows down cell division in human OC cells (West et al., 2020). The Hey OC cell line showed G2 arrest after treatment with DHA, while the ІGRОV-1 OC cell line showed a G1 arrest. Remarkably, G2 arrest in Hey cells was observed only at higher doses of DHA, which is often associated with increased apoptosis (West et al., 2020). GLA (n-6 PUFA) and EPA (n-3 PUFA) enhanced the cytotoxic effects of anticancer drugs such as vincristine, cisplatin, and doxorubicin (Das et al., 1998). Most evidence to date comes from in vitro systems and requires confirmation in clinically relevant models and human cohorts. In particular, “high/low” circulating FA levels are not equivalent to tumor membrane composition or intratumoral lipid signaling, and directionality may differ by histology (e.g., high-grade serous vs. clear-cell OC) and treatment exposure. Some major controversies remain. Some cohort studies have not confirmed a direct association between MUFA intake and GC risk, suggesting that endogenous MUFA synthesis via SCD1 may be a stronger driver of tumor progression than dietary intake (Currie et al., 2013; Röhrig and Schulze, 2016). PUFA subtype effects also appear context-dependent, as n-6 PUFAs can promote inflammation whereas n-3 PUFAs counteract it (Yang and Stockwell, 2016). Tumor heterogeneity, menopausal status, BMI, and metabolic comorbidities further complicate interpretation, emphasizing the need for stratified analyses (Yang and Wang, 2019; Lai et al., 2025). In conclusion, available evidence suggests that MUFA-rich membrane states (often linked to SCD1 activity) may support pro-survival signaling in GC models, whereas n-3 PUFA (e.g., DHA and EPA) more consistently show anti-proliferative and pro-apoptotic effects in experimental systems; however, circulating “high/low” serum levels should not be interpreted as causal without well-controlled prospective human studies. In addition, both n-3 and n-6 PUFA enhance the cytotoxic effects of some anticancer drugs and modulate the tumor microenvironment.

Although FAs are an efficient energy source for some cancer cells, published data suggest metabolic shift favoring glucose over FAs utilization in EC (Knapp et al., 2012). For example, increased expression of glucose transporters (GLUT-1, GLUT-3, GLUT-4) and decreased expression of CD36, FABP4 and FATP-1 was found in EC (Knapp et al., 2012; Miki et al., 2022). Also, our recent study showed decreased CD36 gene expression in cancer tissue of EC patients (Razghonova et al., 2025). FABP4, an adipocyte-specific FA-binding protein, is secreted by adipocytes and can deliver FAs to neighboring tumor cells, thereby coupling the metabolic activity of the stroma to tumor growth (Tian et al., 2020). Interestingly, overexpression of FABP4 in EC has been linked to suppression of PI3K/Akt phosphorylation, resulting in reduced proliferation, migration, and invasion in vitro and suppression of tumor growth in vivo (Wu et al., 2021). Conversely, the addition of lipids to EC cell lines promoted an increase in CD36 levels, stimulates FA uptake, and cell proliferation (Miki et al., 2022). Moreover, CD36 protein levels in EC positively correlated with lymph node metastasis (Miki et al., 2022). Together, these findings support a model in which EC cells show reduced baseline FA import relative to glucose uptake, but lipid availability and microenvironmental inputs can still induce CD36-linked FA uptake and aggressive behavior in some settings.

Іnterestingly, expression of CD36 increases in human CC cell lines exposed to transforming growth factor-β (TGF-β), an epithelial-mesenchymal transition (EMT)-inducing factor (Sun and Zhao, 2022). Knockdown of CD36 in CC cell lines results in reduced cell migration, invasion, colony formation, and increased apoptosis, thus reducing EMT (Deng et al., 2019). Knockdown of FABP4 in CC cells resulted in decreased aggressiveness and increased expression of E-cadherin (protein associated with maintaining cell adhesion and preventing cell migration) and downregulated expression of N-cadherin and vimentin (marker of invasive cell phenotype), as well as p-Akt (involved in cell survival and proliferation) (Li et al., 2021). These data position CD36 and FABP4 as functional contributors to pro-migratory/EMT-linked phenotypes in several CC models, consistent with an FA uptake-supported invasive program.

In OC, metastatic tumor cells exhibit a unique dependency on adipocyte-derived lipids as a metabolic fuel. Adipocytes within the omental niche actively release FA, which are then transferred to OC cells in a process largely mediated by FABP4 (Nieman et al., 2011). This lipid crosstalk is not merely metabolic: it drives tumor proliferation, enhances invasion, and contributes to platinum resistance (Mukherjee et al., 2020). Genetic silencing or pharmacologic inhibition of FABP4 significantly reduces lipid transfer, suppresses tumor growth in xenograft models, and restores chemosensitivity, underscoring FABP4 as a promising therapeutic target (Nieman et al., 2011; Mukherjee et al., 2020). Furthermore, co-culture and in vivo studies demonstrate that adipocyte-OC interactions induce CD36 upregulation, while other transporters (FABPpm, FATP1 and FATP4) are unaffected. Upregulation of CD36 amplify FA uptake and lipid droplet accumulation, elevate ROS and pro-inflammatory cytokines, and activate de novo lipogenesis and cholesterol synthesis programs (Gharpure et al., 2018; Ladanyi et al., 2018). These results underscore FABP4 as a central node linking the adipocyte-rich microenvironment to tumor metabolic reprogramming and metastatic competence (Gharpure et al., 2018). The increase in FABP4 expression was also observed in cell lines representing high-grade serous OC (Mukherjee et al., 2020). Іnterestingly, knockdown of CD36 reduced adipocyte-induced FABP4 expression, whereas knockdown of FABP4 did not affect adipocyte-mediated CD36 expression (Sun and Zhao, 2022). Thus, these data suggest functional and/or regulatory relationship between CD36 and FABP4 in the context of adipocyte-induced changes in cancer cells (Mukherjee et al., 2020). CD36 inhibition also protects against adipocyte-driven EMT and stemness, which are associated with pro-metastatic effects, possibly mediated by FABP4 (Sun and Zhao, 2022). Primary ОC and ОC visceral metastases are characterized by upregulated CD36 expression (Wang et al., 2016). Collectively, in OC adipocyte-driven lipid supply, FABP4-mediated transfer, and CD36-linked uptake form a coherent metastatic metabolic axis (particularly in the omental niche).

Overall, decreased expression of CD36, FABP4 and FATP-1 was found in EC (Knapp et al., 2012; Razghonova et al., 2025). In contrast, upregulation of CD36 and FABP4 was observed in CC (Sun and Zhao, 2022) and OC (Wang and Li, 2019; Mukherjee et al., 2020; Eltayeb et al., 2022). This pattern suggests that EC may rely less consistently on exogenous FA transport than OC and CC in the cited datasets, although lipid uptake can still be induced under specific microenvironmental conditions and requires further validation across EC subtypes. By comparison, multiple preclinical and translational studies support a stronger dependence on adipocyte-linked FA uptake programs (FABP4/CD36) in OC and in several models of CC (Knapp et al., 2012).

In co-culture model, adipocytes displayed elevated lipolysis and released FFAs, which are then taken up by EC cells and oxidized, thereby enhancing their proliferative and invasive capacity (Zhou et al., 2024). Notably, adipocyte-EC cells co-cultures also upregulated SIRT1 signaling in the cancer cells, linking fatty acid β-oxidation (FAO) to transcriptional control of stress responses and EMT (Savardekar et al., 2024). In EC, omics-based studies identified lipid droplet-associated gene signatures and cholesterol synthesis enzymes localized to LDs as potential biomarkers and drivers of tumor progression (Ayyagari et al., 2025).

Increased expression of the gene encoding carnitine palmitoyltransferase 1 (CPT1), an enzyme that plays a key role in the entry of acyl-CoA into the mitochondria for FAO, has been demonstrated in OC cell lines (Shao et al., 2016). Inactivation of CPT1 led to reduction of intracellular ATP levels, induced cell cycle arrest at the G0/G1 phase, and increased susceptibility to metabolic stress, thereby underscoring the essential role of FAO in sustaining OC bioenergetics and survival (Shao et al., 2016). OC cells were also shown to have higher reliance on FAs metabolism compared to control cells (Grasmann et al., 2021; Tondo-Steele and McLean, 2022). Beyond intrinsic tumor metabolism, the tumor microenvironment strongly reinforces FAO dependency. In co-culture systems, adipocyte - OC interactions facilitate direct lipid transfer from adipocytes to cancer cells, primarily via FABP4-mediated shuttling, resulting in enhanced proliferation and metastatic potential (Nieman et al., 2011; Ladanyi et al., 2018). Lipid shuttling is coupled to increased CD36 expression, lipid droplet accumulation, and ROS generation, which further activate stress-adaptive pathways such as NF-κB and promote chemoresistance (Ladanyi et al., 2018). Importantly, FA utilization in GCs is not restricted to immediate oxidation. Cancer cells actively sequester excess FA into lipid droplets (LDs), which function both as energy reservoirs and as buffers protecting against lipotoxicity and ferroptosis (Jin et al., 2023; Safi et al., 2024). During metabolic stress or nutrient deprivation, stored triglycerides in LDs are mobilized through adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), supplying substrates for FAO and sustaining mitochondrial ATP production (Safi et al., 2024; Deswal et al., 2025). This LD-FAO axis is increasingly recognized as a survival mechanism in high-grade serous OC, where elevated LD accumulation independently predicts poor prognosis (Iwahashi et al., 2021).

In summary, FAO and LD metabolism together form a coupled survival network in GCs, integrating energy production, redox homeostasis, and therapy resistance. Future studies should address how FAO inhibitors (e.g., CPT1 blockers) or LD-targeting strategies (e.g., ATGL modulators) can be combined with standard chemotherapy to selectively disrupt this metabolic axis.

The level of lysophosphatidic acid (LPA), a bioactive lipid formed by phospholipases from phosphatidic acid (PA) according to the reaction PA + H₂O → LPA + FA (Geraldo et al., 2021), is significantly increased in the plasma of women suffering from EC (Wang et al., 2010), CC (Wang X. et al., 2022) and OC (Xu et al., 1998). Several findings emphasize the important role of LPA in the proliferation and invasion of EC cells (Wang et al., 2010). Moreover, LPA plays a crucial role in shaping the microenvironment of EC by stimulating the secretion of urokinase plasminogen activator and matrix metalloproteinase-7, which are involved in cancer progression (Wang et al., 2010; Geraldo et al., 2021). Platelet-activating factor (PAF) is produced from polar lipids, especially PC and PE, and regulates inflammation, immune response, and cancer progression (Ashraf and Nookala, 2023). Іt was found that PAF stimulates the proliferation and migration of cancer cells and promotes angiogenesis and tumor invasion in EC (Baldi et al., 1994) and OC (Deuster et al., 2021). Sfingolipids, including ceramides, sfingosine, sphinganine, sphingomyelins, gangliosides and sphingosine-1-phosphate (S1P), which are also components of cell membranes, have numerous functions, including cell signaling, apoptosis and regulation of other physiological and pathophysiological processes (Takai et al., 2005). The concentrations of sphinganine, dihydroceramide, ceramide, sphingosine and S1P were significantly higher in EC tissue than in normal endometrium (Knapp et al., 2017). Ceramide promotes apoptosis, while S1P promotes tumor survival and angiogenesis (Knapp et al., 2019). Thus, ceramide and S1P has been implicated in EC progression (Santin et al., 2004). Interestingly, C2 ceramide (a synthetic ceramide analog) altered the cell cycle by reducing the proportion of cells in S phase and increasing proportion of cells in G0/G1 and/or G2/M phase in Ishikawa EC cells (Takai et al., 2005). C2 ceramide also induces apoptosis and alters the expression of genes encoding proteins associated with cell growth and malignancy (Yu et al., 2011). This suggests that C2 ceramide may be a promising agent for the effective treatment of EC (Takai et al., 2005).

Aberrant levels of PC, PE, PІ, PG and PS in cell membranes promote CC cell proliferation and migration by activating the PІ3K/Akt and MAPK/ERK pathways (Koundouros and Poulogiannis, 2019). LPA was found to a) reduce cell death and chromatin aggregation in cells treated with doxorubicin (DOX) (Wang Q. et al., 2022; Wang X. et al., 2022) downregulate the expression of gene encoding caspase-3 in DOX-treated CC cells (Wang X. et al., 2022) prevent apoptosis in DOX-treated CC cells and d) reduce DOX-induced intracellular ROS levels (Wang Q. et al., 2022). These results suggest that LPA can protect CC cells from DOX-induced apoptosis (Wang K. H. et al., 2022). C8 ceramide (a synthetic ceramide analog) has an antiproliferative and cytotoxic effect on human CC cells infected with papillomaviruses (Bi et al., 2019). C8 ceramide significantly reduces the number of tumor cells and induces necrotic changes (Bi et al., 2019).

Some findings suggested that the levels of specific lipid molecules in cell membranes could be potential diagnostic biomarkers in GC (Preetha et al., 2005; Yagi et al., 2020). For example, Yagi et al. (2020) reported that a) the ratio of LPC(20:4)/LPC(18:0) may be useful for distinguishing patients with benign ovarian masses from healthy controls; b) the ratio of SM(d18:1/24:1)/SM(d18:1/22:0) (the letter ‘d’ refers to the 2 (di-) hydroxyl groups in sphingosine) may help to distinguish OC patients from other groups of gynecological patients; and c) the ratio of PC (18:0/20:4)/PC(18:0/18:1) may be useful to distinguish OC patients from controls. In addition, LPA promotes tumor cell proliferation, migration and invasion by activating LPAR1 and LPAR3 (G protein-coupled receptors) in OC (Balijepalli et al., 2021). Diacylglycerol and Ca²⁺ (known as second messengers) are also involved in LPA signaling and activate downstream pathways including PІ3K/Akt and MAPK/ERK pathways (Kouba et al., 2019). It should be noted that early stage OC patients were more accurately diagnosed by the determination of LPA, PE and LPC in serum than those diagnosed based on CA125 alone (Shan et al., 2012; Yagi et al., 2019). Sutphen et al. (2004) reported that the ratio of LPA/LPI (LPI - lysophosphatidylinositol) in plasma determined by electrospray ionization mass spectrometry (ESI-MS) was higher in patients with EОC. Moreover, reduced plasma LPC levels in EОC patients distinguished them from patients with borderline ovarian tumors (BOTs) (Zhang et al., 2012). Detection of LPA in vaginal secretions is a promising non-invasive diagnostic biomarker for the identification of endometrioid and ovarian malignancies in postmenopausal women (Minis et al., 2019). LPA in serum/plasma has been shown to be a prognostic biomarker for OC (Xu et al., 1998; Xu, 2019; Ikeda et al., 2024) and also a potential biomarker for EC (Wang et al., 2010) and CC (Wang Q. et al., 2022), but evidence for clinical utility remains limited by small cohorts and variable analytical platforms; independent validation is still required. Plasma levels of natural ceramides (C16:0-Cer, C18:1-Cer and C18:0-Cer) were higher in women with advanced OC than in control subjects. In addition, the levels of some natural ceramides (C16:0-Cer, C18:1-Cer, C18:0-Cer, C24:1-Cer and C24:0-Cer) and S1P were elevated in ovarian tissue of women with advanced OC compared to healthy controls (Knapp et al., 2017). Gangliosides are glycosphingolipids, that contain a sphingoid base (mainly sfingosine) and a carbohydrate (mainly glucose or galactose). Elevated levels of gangliosides haven been found in ascitic fluid and plasma of patients with OC (Santin et al., 2004). Іncreased serum levels of gangliosides in OC may be due to the release of gangliosides from the surface of tumor cells (Santin et al., 2004). The glycosphingolipid composition on the surface of OC cells may be an important contributor to EMT status (Santin et al., 2004).

Overall, polar lipids play a complex role in cancer progression by influencing cellular signaling, membrane composition, and interactions with the tumor microenvironment. LPA, ceramides and gangliosides are also promising diagnostic and prognostic biomarkers. However, most studies remain exploratory (often in small case-control cohorts), and translation to clinically actionable biomarkers will require standardized sampling/analytics and independent validation in prospective GC cohorts. Polar lipids involvement in key signaling pathways, including PI3K/Akt and MAPK/ERK, underscores their potential as therapeutic targets. Future research should further investigate the diagnostic utility of polar lipid profiles and their potential for the development of targeted therapies for GC.