Iron is one of the essential trace elements in the human body and serves an important role in human growth and development, energy metabolism, and immune system functions (39). Abnormalities in iron metabolism affect redox reactions, gene regulation, enzymatic reactions and DNA synthesis or repair (40). In the human body, iron has a complex and elaborate circulatory mechanism to ensure its proper distribution, utilization and storage to maintain appropriate and non-toxic cellular iron levels (41). Iron in the body exists in two forms, Fe²⁺ and Fe³⁺, and there are transport carriers and modes for the different forms of iron. Daily intake of dietary iron includes heme iron and non-heme iron (42). They arrive in the intestinal lumen as Fe³⁺ and are reduced to Fe²⁺ by duodenal cytochrome B to be absorbed; non-heme iron in the intestine is absorbed via divalent metal transporter protein 1 (43). Heme iron is then transported into the duodenal epithelium via heme carrier protein 1 and is absorbed, internalized, and broken down into Fe²⁺ and heme oxygenase-1 (HO-1) (44). Thereafter, iron can remain in the enterocytes or enter the bloodstream from the basolateral membrane of intestinal epithelial cells via membrane iron transport protein 1, while being oxidized by ferrous oxidase or ceruloplasmin to produce Fe³⁺ (45). Upon entering the bloodstream, plasma transferrin (TF) spreads the captured Fe³⁺ throughout the cells of the body and is used by various organs to synthesize specific iron-containing components through TF receptor (TFR)-mediated holo-TF endocytosis (46). For example, the liver synthesizes hemosiderin, muscle tissue produces myoglobin and the bone marrow produces red blood cells containing hemoglobin. Cells promote iron uptake primarily through the TF and TFR systems, and Fe³⁺ is reduced to Fe²⁺ by ferric oxide reductase, most of which binds to ferritin to form storage iron, and a small portion enters the cytoplasm to collectively form the labile iron pool (47). Due to the instability and high oxidizability of Fe²⁺, excess iron ions catalyze the production of reactive oxygen species (ROS), which promotes lipid peroxidation through the Fenton reaction (48), thereby causing oxidative damage to lipid membranes, proteins and DNA, and ultimately leading to cell death (49). Among the three main mechanisms of ferroptosis, excessive accumulation of Fe²⁺ in the labile iron pool increases the sensitivity of cells to ferroptosis and is the initial component responsible for ferroptosis (47).

To the best of our knowledge, the initial signal for ferroptosis has not yet been identified, but ferroptosis is closely related to the levels of intracellular free iron content (50). Iron metabolism serves a key role in the pathophysiology of OC, and the degree of intracellular iron accumulation serves a decisive role in the course of OC (51). Concurrently, abnormalities in iron metabolism, especially the acquisition and retention of excess iron, contribute to tumorigenesis and tumor growth (52,53). Iron accumulation increases the risk of diseases such as cancer and damage to tissues (54). Therefore, maintaining homeostasis of intracellular iron ions is critical. According to Basuli et al (55), OC-initiating cells show high iron dependence. Increased iron efflux also decreases the proliferation and invasion of OC-initiating cells, and conversely increased iron uptake increases OC cell proliferation and invasion. High-grade serous OC (HGSOC) typically originates from the fallopian tube and is diagnosed at a later stage, and it has been observed that the iron content of HGSOC is higher than that of normal ovarian tissues and low-grade serous OC, suggesting that there is a strong association between HGSOC and iron metabolism (56). In addition, the malignant transformation and metastasis of cancer cells are closely associated with changes in cellular redox status (57). The molecular damage caused by the excessive and harmful ROS catalyzed by free iron is often referred to as 'oxidative damage', and Bauckman et al (58) reported that ROS can transform normal ovarian tissue into cancerous tissue by promoting the MAPK pathway. In addition, ROS can hydroxylate DNA residues to generate the highly mutagenic 8-hydroxy-2′-deoxyguanosine, elevated levels of which have been found to be associated with a poor prognosis in patients with HGSOC (59,60). Iron polyporphyrin heme binds to p53, interfering with p53-DNA interactions, leading to nuclear export and cellular degradation of p53, and increased susceptibility to HGSOC (61,62). Basuli et al (55) demonstrated that excess iron simultaneously affects tumor cell proliferation, metabolism and metastasis. Increasing the expression of ferroportin on cell membranes (63), decreasing iron intake (64), or decreasing the concentration of TF (65) and TFR in vivo (66) can inhibit tumor growth. In addition, iron metabolism can contribute to the development of OC by regulating hypoxia-inducible factor (HIF). HIF-1α induces OC progression by inhibiting p53 function, promoting IL-6 expression or being regulated by long non-coding RNAs (67,68). Iron metabolism is also closely related to resistance to chemotherapy, and solute carrier family 40 member 1 (SLC40A1), an iron metabolism-related gene, which is the only known iron-exporting gene (69), serves a crucial role in transporting iron from the intracellular environment to the extracellular environment, and thus, the physiological expression of SLC40A serves a vital role in the regulation of iron homeostasis. SLC40A1-induced iron overload leads to cisplatin resistance in OC (70). Upregulation of SLC40A1 reduces cisplatin resistance by exporting iron, decreasing the intracellular iron concentration and oxidative stress. By contrast, an increase in the intracellular iron concentration and enhanced oxidative stress induced by the downregulation of SLC40A1 increase cisplatin resistance (70). Thus, modulating iron levels to influence the redox system may be a potential strategy to reverse drug resistance in OC therapy.

The iron-dependent nature of OC tumor-initiating cells also makes them sensitive to drugs that induce ferroptosis, as well as to iron chelators, providing a potential therapeutic approach for the management of OC (71). Desferrioxamine (72), a natural iron chelator used in the treatment of iron overload, has shown promising results in the treatment of OC. Wang et al (72) assessed the effects of desferrioxamine on OC cell lines and found that it not only inhibited OC stem cells but also enhanced cisplatin efficacy, improved resistance to chemotherapy and increased the length of survival. There are also drugs that regulate iron metabolism in several ways and may have effects on other biological processes. For example, artemisinin is known for its anti-malarial, anti-inflammatory and antitumor effects, and its compounds (artesunate) can reduce cell proliferation and induce ROS production in OC cells (73). In addition, artesunate can activate the function of lysosomes, promote the degradation of ferritin and lead to the release of iron in lysosomes, and thereby mediate cell death (74). Regulators, including iron uptake-related regulators (75), iron storage-related regulators (76) and iron transport-related regulators (77), influence the pathological process of OC through the regulation of iron metabolism levels.

Ferroptosis is an iron-dependent non-apoptotic cell death mechanism caused by iron-dependent membrane lipid peroxidation and massive accumulation of cellular ROS (78). Membrane lipids serve an important role in the regulation of cell fate and lipid metabolism, which is fundamental in determining the fate of ferroptosis (79), and is similarly critical for ferroptosis execution.

Among various lipids, polyunsaturated fatty acids (PUFAs) associated with several phospholipids such as phosphatidylethanolamine and phosphatidylcholine are responsible for inducing lipid peroxidation in ferroptosis. Phospholipids containing PUFAs are susceptible to oxidation, but less oxidizable saturated/monounsaturated fatty acids protect cells from ferroptosis (80). Thus, the enzymes and pathways that regulate the metabolism of PUFAs and monounsaturated fatty acids, as well as the balance of PUFAs and monounsaturated fatty acids in membrane phospholipids, can influence cellular sensitivity to ferroptosis (81). The findings of the aforementioned study provide a novel strategy for lipid peroxidation treatment of OC ferroptosis. Since the membrane phospholipids of PUFAs that drive ROS production catalyzed by iron ions interacting with PUFAs are responsible for triggering lipid peroxidation leading to cellular ferroptosis, and not free PUFA itself, the enzymes that bind free PUFA to phospholipids serve a crucial role in ferroptosis (81). Acyl-CoA synthetase long-chain family member 4 is an essential component of ferroptosis execution as shown by microarray analysis of ferroptosis-resistant cell lines and using a genome-wide CRISPR-based genetic screening system (82). Under the catalytic action of Acyl-CoA synthetase long-chain family member 4, free long-chain fatty acids are converted to acyl-CoA by linking with CoA. Acyl-CoA inserts into membrane phospholipids and binds to phosphatidylethanolamine to form PUFA phospholipids catalyzed by lysophosphatidylcholine acyltransferase 3 (83). Lipid peroxidation, via two primary mechanisms, non-enzymatic spontaneous oxidation and enzyme-mediated lipid peroxidation (84), results in the production of phospholipid hydroperoxides (PLOOHs), and if antioxidants do not convert PLOOH to phospholipid hydroxides (PLOHs) in a timely manner, the resulting accumulation of PLOOH leads to extensive lipid peroxidation and activation of the antioxidant system, directly inducing damage to cell membranes and ultimately leading to cell dysfunction and ferroptosis (85). Non-enzymatic lipid peroxidation (also known as lipid autoxidation) is a free radical-driven chain reaction. Hydroxyl radicals (OH·) are generated through the reaction of H₂O₂ with Fe²⁺, which reacts with PUFAs in the plasma membrane in a Fenton reaction to generate LPO, leading to ferroptosis (86,87). Enhanced accumulation of LPO is therefore necessary to increase the efficiency of ferroptosis (88), and OH· is the most active ROS (89), and thus, it also serves as an emerging cancer treatment target for the management of OC via chemodynamic therapy. H₂O₂ nano-enzymes developed by Sun et al (90) using CoNi alloys encapsulated with nitrogen-doped carbon nanotubes exhibited glucose oxidase and lactate oxidase activities to effectively disrupt the antioxidant defense system by catalyzing the formation of OH·, increasing ROS content in the tumor microenvironment and damaging the tumor cells, while depleting glutathione (GSH) to induce ferroptosis of the cells. Liang et al (91) demonstrated that polydopamine-mediated Michael addition combined with Fe²⁺ depletion of GSH enhanced OH· accumulation and ultimately resulted in the intracellular release of the chemotherapeutic drug doxorubicin, thus inducing ferroptosis. In addition, lipid peroxidation is tightly regulated by various metabolic and signaling pathways, such as the cytochrome P450 oxidoreductase pathway, and iron-containing enzymes, including lipoxygenase, also contribute to the process of lipid peroxidation (92). Enzymatic lipid peroxidation, conversely, is a process of direct oxidation of free PUFAs into various types of lipid hydroperoxides catalyzed by lipoxygenase (93,94). Among them, the arachidonic acid lipoxygenase family regulates lipid peroxidation. It has been shown that the binding of 5-lipoxygenase to microsomal GSH S-transferase 1 led to a decrease in lipid peroxidation and mediated ferroptosis in cancer cells (95). 12-lipoxygenase, conversely, has been identified as a key factor in p53-mediated ferroptosis under conditions of ROS-induced stress (96), while the expression levels of 15-lipoxygenase are associated with the spermine/spermine N1-acetyltransferase 1 gene, a transcriptional target of p53 (97). Zhang et al (98) demonstrated that chemotherapeutic drugs for OC induced excessive lipid peroxidation through ROS and initiated ovarian cell ferroptosis, thus leading to ovarian cell death. A study (99) has demonstrated that p53 serves an important role in the ferroptosis process. p53 exhibits a bidirectional regulatory effect based on specific environmental conditions. When lipid peroxidation levels are low, p53 inhibits the occurrence of ferroptosis, promoting cell survival. However, when excess lipid peroxidation persists, ferroptosis is induced (99).

In summary, further studies on the effects of various lipid metabolic pathways on lipid peroxidation and ferroptosis from the perspective of chemotherapy-induced oxidative stress and ferroptosis may help control ovarian damage and improve the quality of life of patients with OC. All of them will provide a deeper understanding of ferroptosis and therapeutic strategies for OC.

Oxidative damage occurs due to an imbalance between the cellular antioxidant system with the production of free radicals and/or the neutralization or elimination of their deleterious effects. ROS-mediated lipid peroxidation is a key step to drive cellular ferroptosis, and inactivation of the antioxidant system is the primary cause of ferroptosis (100). At present, it has been shown that the primary antioxidant systems regulating ferroptosis include the System Xc⁻-GSH-GSH peroxidase 4 (GPX4) pathway, the ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) pathway, the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway and the dihydroorotate dehydrogenase (DHODH)-CoQ10H₂ pathway. Among these, the System Xc⁻-GSH-GPX4 pathway is the most fundamental antioxidant system, which serves a key role in protecting cells from ferroptosis (101). An overview of the primary antioxidant systems regulating ferroptosis is shown in Fig. 1.

The System Xc^—GSH-GPX4 pathway serves a key role in the antioxidant defense mechanism of ferroptosis. System Xc⁻ is a cystine-glutamate reverse transporter protein composed of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (102). System Xc⁻ oxidizes intracellular cystine to cysteine, which is further converted to GSH (103). By contrast, GPX4 protects cells against ferroptosis by reducing reactive PLOOH to nontoxic PLOH, which involves GSH (the reducing cofactor of GPX4) (104). Inhibition of GPX4 induces lipid ROS accumulation and induces the onset of ferroptosis, thereby inhibiting tumor cell proliferation (105).

Studies have shown that erastin (38), sorafenib (106), sulfasalazine (107) and p53 (108) could cause GSH production and induce ferroptosis by inhibiting System Xc⁻. Metallothionein-1G is a key factor and potential therapeutic target for regulating sorafenib resistance in human hepatocellular carcinoma. Downregulating metallothionein-1G increases lipid peroxidation and GSH depletion, leading to ferroptosis in hepatocellular carcinoma (106). Yuan et al (109) used an innovative approach, employing a combination of chemotherapy and chemokinetic therapy, which inhibited malignant cell proliferation by inactivating GPX4 by inducing GSH depletion, and this approach showed a high degree of biosafety. Luo et al (110) found that paired box 8 (PAX8) (a GPX4-dependent OC susceptibility gene) depletion sensitized OC cells to GPX4 inhibitors. The combination of PAX8 inhibitor and RSL3 inhibited proliferation and induced ferroptosis in OC cells (110). In addition, the System Xc⁻-GSH-GPX4 pathway is a key antioxidant system that prevents lipid peroxidation-mediated ferroptosis, and blocking this pathway promotes the onset of ferroptosis in tumor cells and prevents chemotherapeutic resistance (111). Okuno et al (112) reported that the System Xc⁻ transporter, which is involved in the transport of cystine and glutamate, had a regulatory effect on intracellular GSH levels and cisplatin resistance in OC cell lines. The results revealed that cisplatin-resistant variant OC cells had an ~4.5-fold higher rate of cystine uptake and higher intracellular GSH levels than OC cell lines due to the acquisition of cystine transporter activity mediated by the System Xc⁻; however, the GSH levels were decreased following glutamate overdose. Cystine uptake was also inhibited. It is therefore suggested that System Xc⁻ serves an important role in maintaining higher levels of GSH and can confer cisplatin resistance in OC cell lines. In addition, a study has shown that the release of GSH and cysteine in OC fibroblasts contributes to the reduction of nuclear accumulation of platinum (112). Additionally, CD8⁺ T cells can inhibit this resistance by regulating GSH and cysteine metabolism in fibroblasts (113).

In summary, inhibition of System Xc⁻, depletion of GSH and reduction of GPX4 activity all mediate metabolic processes involving amino acids that increase sensitivity to ferroptosis-inducing agents, and targeting this system may reverse chemotherapeutic resistance and reduce the rate of OC progression.

Bersuker et al (114) identified FSP1 as a potent resistance factor to ferroptosis, arguing that the FSP1-CoQ10-NADPH pathway is independent of the classical System Xc⁻-GSH-GPX4 pathway, highlighting another pathway involved in the antioxidant regulation of ferroptosis and suggesting that its pharmacological inhibition may render cancer cells sensitive to ferroptosis-inducing chemotherapeutic agents. FSP1 is a key protein that prevents cells from undergoing ferroptosis, and knockdown of FSP1 increases the sensitivity of cell lines to ferroptosis-inducing agents, as well as being a positive regulator of mitochondrial apoptosis. FSP1 is recruited to the plasma membrane via myristoylation, thereby inhibiting ferroptosis (114,115). FSP1 is primarily associated with the outer mitochondrial membrane and undergoes myristoylation at the N-terminus to promote the transfer of CoQ10 from mitochondria to the cell membrane. The NADPH-catalyzed reduction of CoQ10 to ubiquinol-10 (CoQ10H₂) traps free radicals mediating lipid peroxidation, and thus prevents ferroptosis of cells (114). In addition, it has been shown that downregulation of stearoyl-CoA desaturase-1 was followed by a reduction in the lipophilic antioxidant CoQ10, which induced the potential for ferroptosis by inhibiting intracellular synthesis of protective lipids. Inhibition of stearoyl-CoA desaturase-1 enhanced the antitumor effects of ferroptosis inducers in OC cell lines. Combining stearoyl-CoA desaturase-1 inhibitors with ferroptosis inducers may offer a novel treatment option for the management of OC (116). The small molecule compound FIN56 inhibits CoQ10 synthesis in the mevalonate pathway by binding to and activating squalene synthase, resulting in a decrease in CoQ10 levels, and thus, increasing sensitivity to ferroptosis (117).

Nanogels developed by Yang et al (118) enhanced cellular lipid peroxidation through inhibition of the FSP1-CoQ10-NADPH pathway, leading to ferroptosis of immunogenic cells, and resulting in effective tumor ablation and immune responses in a mouse breast cancer model. Furthermore, downregulation of FSP1 in hepatocellular carcinoma cells promoted sorafenib-induced ferroptosis (119).

Therefore, the FSP1-CoQ10-NADPH pathway may complement and work with the System Xc⁻-GSH-GPX4 pathway to inhibit lipid peroxidation in ferroptosis, providing a potential therapeutic strategy for the treatment of OC.

A previous study has identified the GCH1-BH4-DHFR pathway as an alternative compensatory mechanism for the System Xc⁻-GSH-GPX4 pathway (120). GCH1 is the rate-limiting enzyme for BH4 biosynthesis, which promotes ferroptosis via the metabolites BH4 and dihydrobiopterin (BH2). BH4 acts as a free radical trapping antioxidant that can be recycled by DHFR for redox cycling, and BH4 has antioxidant degradation effects on phospholipids containing two PUFA tails and prevents lipid peroxidation and thus ferroptosis by inhibiting the production of specific LPOs (120,121).

Through the direct trapping of antioxidant free radicals and the production of CoQ10 (120), when GCH1 is upregulated, it promotes BH4 production and abrogates the deleterious effects of RSL3-induced cellular ferroptosis. Additionally, overexpression of GCH1 has been shown to decrease the sensitivity of drug-resistant cancer cells to ferroptosis, which in turn further ameliorated the progression of ferroptosis in cancer cells through the regulation of CoQ10 (122).

In addition, relevant studies have shown that BH4 is involved in the synthesis of dopamine, nitric oxide synthase and melatonin (123), whereas exogenous dopamine or melatonin can inhibit ferroptosis (124). Several studies have shown that nitric oxide can induce or inhibit ferroptosis in tumor cells depending on environmental conditions (125-127). DHFR reduces BH2 through the involvement of NADPH, thereby promoting BH4 synthesis. If DHFR is inhibited, ferroptosis of tumor cells is promoted via the synergistic action of GPX4 inhibitors (87).

Therefore, the GCH1-BH4-DHFR pathway serves a role in regulating the balance between oxidative damage and antioxidant defense during ferroptosis and interacts with the System Xc⁻-GSH-GPX4 pathway and the FSP1-CoQ10-NADPH pathway in a synergistic or complementary manner. Although other specific mechanisms and potential therapeutic targets remain to be determined, the identified pathways may serve as potential therapeutic targets for overcoming resistance to chemotherapy in OC.

The mitochondrial DHODH-CoQ10H₂ pathway and the FSP1-CoQ10-NADPH pathway are the two major lipid antioxidant systems in mitochondria. If one system is inhibited, the cell becomes more dependent on the other antioxidant system, and if both systems are inhibited, mitochondrial lipid peroxidation occurs, resulting in ferroptosis (128).

CoQ10H₂, a free radical trapping antioxidant with anti-ferroptotic activity. DHODH is located on the outer surface of the inner mitochondrial membrane and inhibits cellular ferroptosis by converting CoQ10 to CoQ10H₂ to reduce lipid ROS in mitochondria. In addition, supplementation with dihydroorotate or orotate, substrates or products of DHODH, attenuates or enhances the inhibitory effect of GPX4, respectively, thereby modulating cellular ferroptosis (129).

The mitochondrial DHODH-CoQ10H₂ pathway and the FSP1-CoQ10-NADPH pathway function independently of each other, but they both reduce CoQ10 to CoQ10H₂ to enhance the mitochondrial defense mechanism against ferroptosis.

IRE1 consists of two isoforms, IRE1α and IRE1β; IRE1β is primarily expressed in the respiratory and gastrointestinal tracts, whereas IRE1α is more widely expressed (133). The cytoplasmic tail of IRE1α has two domains, a serine/threonine kinase structural domain and a ribonuclease (RNase) structural domain, which work together (134). The kinase of IRE1α is activated upon binding to misfolded proteins and undergoes dimerization/coupling and trans-autophosphorylation, leading to ectopic activation of the structural domain of RNase (135). Under the catalysis of active RNase, the intron containing 26 nucleotides is excised from the mRNA encoding the homeostasis transcription factor X-box protein 1 (XBP1). Then, two mRNA fragments are cleaved by RNA splicing ligase RNA 2′,3′-cyclic phosphate and 5′-OH ligase, thereby generating the stable active transcription factor XBP1s (spliced form) (136,137). XBP1s (spliced form) is involved in the expression of genes encoding ER membrane biogenesis, ER protein folding, ER-associated degradation and multiple UPR targets (138). C/EBP homologous protein (CHOP), a major regulator of ERS-induced apoptosis, is activated by activating transcription factor 4 (ATF4) through the PERK-ATF4-CHOP pathway (139). In addition, IRE1α promotes apoptosis by activating the apoptosis signal-regulating kinase 1/JNK pathway, and by binding to tumor necrosis factor receptor-associated factor 2 (140). In addition, regulated IRE1-dependent decay is a novel UPR-regulated pathway that has been identified to control cell fate under ERS. Activated RNase can target other mRNAs and microRNAs (miRs) by regulating this pathway (141).

Zundell et al (142) showed that pharmacological inhibition of the IRE1α/XBP1 pathway may serve as a novel therapeutic strategy for Arid1a-mutant cancers, and that knockdown of the XBP1 gene improved survival in mice harboring Arid1a-inactivated ovarian clear cell carcinomas. Song et al (143) demonstrated that controlling ERS or targeting IRE1α-XBP1 signaling modulated mitochondrial activity, and thus, may help control T-cell metabolic adaptations and anti-tumorigenic capacity in patients with OC. The mitochondria-associated ER membrane can also serve as an important link between the mitochondria and the ER (144). Cubillos-Ruiz et al (145) showed that the IRE1α-XBP1 pathway of dendritic cells in the OC microenvironment was continuously activated due to sustained ERS, which disrupted the antigen-presenting capacity and metabolic homeostasis of the dendritic cells and diminished their protective function in supporting of T cells against tumors, highlighting a unique immunotherapeutic approach for the management of OC. OC cells utilize ERS for survival through activation of the IRE1α/XBP1s pathway among other pathways, and coactivator associated arginine methyltransferase 1 (CARM1), which is typically upregulated in OC cells, has been revealed to regulate the expression of XBP1s target genes and to be selectively sensitive to the inhibition of the IRE1α/XBP1s pathway, providing a potential therapeutic strategy for the treatment of CARM1-expressing OC (146).

PERK is a type I transmembrane protein with similarities to IRE1, which has an ER lumenal dimerization structural domain and a cytoplasmic kinase structural domain. The tubulin dimerization structural domain of PERK has less sequence similarity to IRE1 but is structurally and functionally similar to the structural domain of IRE1. The cytoplasmic kinase structural domain of PERK also undergoes trans-autophosphorylation in response to ERS, but it differs from IRE1 in that PERK also phosphorylates the eukaryotic translation initiation factor 2α (eIF2α) at serine 51, and phosphorylated eIF2α inhibits overall translation of proteins, and thus, reduces the amount of proteins entering the lumen of the ER (147,148). In addition, phosphorylation of eIF2α alters the utilization efficiency of the AUG start codon (149), which results in preferential translation of the ATF4 mRNA (148).

ATF4 is a transcription factor that activates downstream UPR target genes, such as the expression of growth arrest DNA-damage 34 (GADD34), which induces CHOP expression (148,150). CHOP promotes DNA damage, inhibits cell proliferation and activates apoptosis by upregulating the pro-apoptotic members of the B-cell lymphoma-2 family of proteins (151). Therefore, ATF4 serves an important role in ER-functional gene expression, ERS-mediated ROS production and ERS-induced apoptosis. ATF4 can also regulate the dephosphorylation of eIF2α through GADD34 to form an inhibitory feedback loop to reverse PERK-mediated translational decay (152). In addition, PERK phosphorylates nuclear factor erythroid 2-related factor 2 (Nrf2), thereby upregulating antioxidants to promote cellular antioxidation (153). Overall, the PERK-eIF2α pathway first mediates the promotion of cell survival during ERS but shifts to the promotion of apoptosis when ERS is sustained and maintains cellular homeostatic balance by activating ATF4 and NRF2. Therefore, the PERK pathway is an attractive therapeutic target in OC therapy.

ATF6 is a type II transmembrane protein with a carboxy-terminal stress-sensing lumenal structural domain and an amino-terminal bZip transcription factor structural domain (154). ATF6 is transported to the Golgi under conditions of ERS, where it is sequentially hydrolyzed by serine protease site 1 and metalloprotease site 2 (S2P) proteins to release its amino-terminal transcription factor structural domain, which, synergistically with XBP1, upregulates genes involved in protein folding and ER amplification, as well as genes involved in ER-associated degradation pathway components (155). It has been shown that ATF6 expression in OC tumor tissues is higher than that in normal ovarian tissues (156), and under irreversible ERS, it downregulates the levels of anti-apoptotic proteins (157). In addition, by regulating ATF6, the sensitivity of OC cells to chemotherapeutic agents can be altered (158). However, the role of ATF6 in ER-induced cell death and co-targeting of chemotherapeutic agents to improve survival in OC still needs to be explored further.