In a study, the researchers utilized the organoid model of ovarian cancer to validate the hypothesis that abnormally overexpressed serine/threonine kinase Aurora-A directly phosphorylates sex-determining region Y-box 8 (SOX8) at Ser327 or indirectly enhances SOX8 transcription via c-Myc (33). Subsequently, SOX8 targets HK2 and lactate dehydrogenase (LDHA), which affect the glycolysis process via the SOX8/FOXK1 axis, ultimately leading to drug resistance ( Table 1 )

Zhang XY et al. (34) shows that HK2 presents resistance to cisplatin in the ovarian cancer cell, promotes the resistance by enhancing cisplatin-induced autophagy, and boosts the cisplatin-induced autophagy by activating the ERK1/2 pathway. The upregulation of HK2 expression and subsequent drug resistance can be attributed to the effects of lysophosphatidic acid (LPA) (35). HK2 is expressed on mitochondria in cancer cells and interacts with voltage-dependent anion channel 1 (VDAC1) to impede apoptosis ( Figure 1 ). Notably, studies have demonstrated that peroxisome proliferator-activated receptor coactivator 1 (PGC1α) (36), which is highly expressed in drug-resistant ovarian cancer cells, promotes the transcription of α heat shock protein (HSP70). Consequently, the upregulation of HSP70 leads to increased expression of HK2 on mitochondria, and its binding to VDAC1. Therefore, the HSP70/HK2/VDAC1 signaling pathway may serve as a potential target for therapies.

Platinum-resistant ovarian cancer cells exhibit increased levels of pyruvate dehydrogenase kinase 1 (PDK1) in comparison to platinum-sensitive cells. The study by Zhang M et al. revealed that upregulated PDK1 activates epidermal growth factor receptor (EGFR) to facilitate the development of chemotherapy resistance (37). Notably, downregulating PDK1 in drug-resistant cells enhances the sensitivity to cisplatin-induced cell death. Despite these findings, the precise mechanism of action remains unclear.

Van Nyen T, et al. (38) explored the relevance of phosphoglycerate dehydrogenase (PHGDH) expression and serine biosynthesis activity in tumors with acquired platinum resistance after platinum chemotherapy. They recognized a subset of ovarian cancer patients who relapsed after platinum-based chemotherapy with decreasing in PHGDH expression. Then, through in vivo, in vitro, and metabolic pathways tests, they investigated that this subgroup had undergone metabolic changes of decreased serine biosynthesis, which caused tumor cells to need exogenous serine for metabolic activities. This metabolic shift is accompanied by a regenerative phenotype of NAD+. Although tumor cells have no significant change in NAD+ levels, NAD+ regeneration is active and benefits from maintaining PARP’s activity to resistant platinum.

While the role of aerobic glycolysis in tumors has been extensively studied, recent research suggests that mitochondrial oxidative phosphorylation (OXPHOS) may also contribute to platinum resistance in ovarian cancer.

Platinum-based chemotherapy agents may induce an increase in NAD⁺-dependent deacetylase SIRT1 (39), which in turn promotes OXPHOS and enriches chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSC), ultimately leading to drug resistance. However, the precise mechanisms underlying this phenomenon require further investigation. Furthermore, as a critical modulator of the mitochondrial respiratory chain (40), downregulation of the TRAP1 chaperone protein inhibits glycolysis in tumor cells and shifts metabolism towards OXPHOS, which in turn promotes the release of various inflammatory factors, including IL-6, to stimulate an inflammatory response that reduces platinum sensitivity in ovarian cancer cells (41).

As a classic treatment for diabetes, metformin may play a therapeutic role by exploiting the metabolic changes of platinum-resistant ovarian cancer, which is conducive to the cytotoxic effect of platinum drugs and prevents the progression of tumor cells. Metformin has been identified as a promising drug to overcome resistance to platinum-based therapy in ovarian cancer. The mechanism of action involves targeting mitochondrial complex I and ATP synthases, leading to a partial reversal of resistance (42). Metformin also regulates apoptosis by downregulating Bcl-2 and Bcl-xL expression and upregulating Bax and Cytochrome expression (43). Moreover, metformin has been shown to reduce inflammation and improve drug sensitivity by inhibiting the NFκB signaling pathway and IL-6 secretion (44, 45). Furthermore, metformin can reverse resistance via the p53-PDK1-HKII pathway and by activating the AKT signaling pathway while inhibiting the IGF2R signaling pathway (46, 47). Notably, metformin can also modulate the metabolic profile of resistant cells by upregulating taurine and histidine levels and downregulating tyrosine kinase levels, thus preventing chemoresistance (48, 49). In summary, the combination of metformin and cisplatin presents a promising therapeutic strategy for preventing drug resistance in ovarian cancer cells with metabolic alterations.

Fatty acid β-oxidation has been linked to platinum resistance (54), with genetic ablation of the homology box-containing developmental regulator NKX2-8 promoting fatty acid metabolism reprogramming and subsequent drug resistance in epithelial ovarian cancer cells in the adipose microenvironment (55). Additionally, a novel biomarker, Collagen type XI alpha 1 (COL11A1) (56), has been found to induce platinum resistance by upregulating fatty acid metabolism in ovarian cancer through its binding to discoid domain receptor 2 and activating Src-Akt-AMPK signaling. Furthermore, activation of the transcription factor c-JUN α diacylglycerol kinase (DGKA) leads to the recruitment of c-JUN N-terminal kinase to c-JUN and enhances the expression of the cell cycle regulator WEE1 under cisplatin stimulation, ultimately leading to platinum resistance in ovarian cancer (57).

In the context of ovarian cancer, FABP4 plays a central role in regulating adipocyte-induced lipid metabolism in cancer cells (58). Its overexpression promotes tumor proliferation and metastasis and mediates drug resistance to carboplatin. However, the downstream factors and pathways that specifically mediate drug resistance of FABP4 remain unclear. Adipocytes can also inhibit cisplatin-induced apoptosis by secreting arachidonic acid, which activates Akt (59). Moreover, the SP1-12LOX axis can upregulate the expression of multidrug resistance-associated protein (MRP) via signal transduction, increase the production of arachidonic acid-derived metabolites, and promote drug resistance (60).

Cholesterol metabolism dysregulation can be a contributing factor to platinum resistance in ovarian cancer, as cholesterol is a vital component of cell membranes and plasma lipoproteins and a precursor for important bioactive molecules (61). The decrease in TRAP1 expression, as mentioned earlier, also impacts cholesterol metabolism. In drug-resistant ovarian cancer cells, exogenous uptake becomes the primary source of cholesterol, with decreased expression of farnesyl bisphosphate synthase (FDPS) and oxidized squalene cyclase (OCS) involved in endogenous cholesterol synthesis, and increased expression of low-density lipoprotein receptor (LDLR) promoting exogenous cholesterol uptake (62). Furthermore, carboplatin-resistant ovarian cancer cells exhibit upregulation of ADP ribosylation factor 4C (ARL4C), a member of the ADP ribosylation factor subfamily, and Notch-RBP-Jκ-H5K3Me4, a member of the oxysterol-binding protein family (OSBP), resulting in the upregulation of OSBPL5, a member of the OSBP family, promoting cholesterol accumulation and autophagy, leading to carboplatin resistance (63). Malignant ascites exhibited elevated cholesterol levels, with upregulated drug efflux proteins ABCG2 and MDR1, and cholesterol receptor LXRα expression, contributing to multidrug resistance (64).

Glutamine, the most abundant non-essential amino acid in the human body, serves a multitude of purposes, including its function as a key substrate or molecule in the biosynthesis of various compounds, and its essential role in maintaining normal cellular function and integrity (71). Aside from relying on aerobic glycolysis, drug-resistant ovarian cancer cells exhibit an addiction to glutamine (72). DNA methylation has been found to regulate the expression of the critical enzyme glutamine synthetase, resulting in the metabolic reprogramming of glutamine in tumor cells (73). Preferentially directing glutamine towards glutathione (GSH) synthesis instead of the TCA cycle ultimately leads to increased levels of glutamine, glutamic acid, and glutathione. Despite the sensitivity of drug-resistant tumor cells to nutrient deficiencies, glutamine can combat starvation-induced cell death by increasing nucleotide concentrations (74).

GSH is synthesized from glutamic acid, cysteine, and glycine and is one of the important members of cellular antioxidants (75). GSH depletion in tumor cells can increase the attack of chemotherapy drugs on tumor cells through reactive oxygen species (ROS) accumulation, detoxification reduction, and iron death to achieve therapeutic purposes (76). Non-targeted metabolomics analyses showed that platinum-resistant ovarian cancer cells have significantly reduced levels of GSH, which contributes to chemoresistance by forming adducts with cisplatin, leading to reduced intracellular concentrations of the active drug, and cisplatin-GSH adducts also reduce intracellular GSH levels. And these resistant cells can activate alternative antioxidant defenses independent of GSH (77). Cysteine stored in large quantities in GSH has a protective effect on ovarian cancer cells in a hypoxic environment and can also make tumor cells resistant to carboplatin (78, 79) ( Figure 2 ).

In the context of arginine deficiency, Omental adipose stromal cells (O-ASC) have been shown to stimulate tumor cell growth and NO synthesis by secreting arginine (80). The uptake and transport of arginine across cell membranes are mediated by cationic amino acid transporters, specifically SLC7A1/CAT1, which are highly expressed in ovarian cancer and are involved in the metabolic reprogramming of arginine, ultimately promoting platinum resistance (81). Furthermore, studies have shown that ovarian cancer cells with elevated levels of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme that catalyzes the conversion of tryptophan to l-kynurenine (Kyn), exhibit platinum resistance by downregulating the ROS/p53 pathway (82). Hence, it is important to further investigate the role of arginine transport and IDO1 in the development of platinum resistance in ovarian cancer cells.