Calcium ions (Ca²⁺) serve as the secondary messengers within cells, regulating a myriad of cellular processes. MAMs, significant bridges for Ca²⁺ transport, finely tune Ca²⁺ signal transmission ensuring precise and flawless execution of cell biological functions. At present, two primary types of Ca²⁺ release channels have been well-understood in MAMs, namely: IP3Rs and RyRs.

The IP3Rs, voltage-dependent anion channels that dominate Ca²⁺ release above MAMs, collaborate with GRP75 and VDAC to take on this formidable task. The tripartite protein complex assists calcium ions in traversing from mitochondria to ER.

Another primal ER protein SEPN1, abundant in this type of MAMs, can replenish calcium ions on the ER when it is depleted, thus circumventing ER stress. Besides protecting IP3R from oxidative harm by Ero1a, SEPN1 also upholds calcium ion equilibrium between MAMs, mitochondria and ER (6).

Existing in the same form as a protein complex are Sig-78 and immunoglobulin. When calcium ions are depleted in the ER, Sig-78 dissociates from the complex and interacts with IP3Rs, substantially enhancing Ca²⁺ influx into mitochondria. Moreover, Ero1a, an oxidase residing in MAMs, prompts calcium ion flux towards mitochondria when faced with ER stress by oxidative binding to IP3R, thereby activating IP3R (7,8).

Lastly, glutathione peroxidase 8 (GXP8), a bipolar transmembrane protein present in MAMs, can lower calcium level on the ER by suppressing the activity of SERCA when overexpressed. Also acting similar to GXP8 is the redox enzyme TMX1 located on the ER, again by preventing the action of SERCA. SERCA plays a core role in the transportation process of calcium ions. It regulates the content of intracellular Ca²⁺ ions and profoundly influences the flow of calcium ions in MAMs. When the pressure on the ER becomes excessive, the activity of SERCA1 dramatically escalates, thereby propelling calcium ions from the ER to mitochondria, culminating in mitochondrial apoptosis (7,8).

Moreover, mitochondria demonstrate their unique role during the transport of calcium ions over a short time period. Upon the transfer of calcium ions from the ER to MAMs (7,8), high calcium concentration regions often emerge macroscopically. Under this state, the speed at which mitochondria absorb calcium ions markedly accelerates. By contrast, when calcium ion concentration is low, the efficiency of mitochondria in absorbing calcium ions noticeably decreases. Therefore, the regulation of calcium ion concentration is indeed heavily influenced by a profound impact led by MAMs. Besides, existing research has unveiled that mitofusin 2 (Mfn 2) is a pivotal target for regulating calcium ion concentration in MAMs; however, some studies have yielded contrary experimental conclusions (9). Thus, there still remains considerable research exploration space in terms of how MAMs affect the degree of influence on the flow of calcium ions between mitochondria and ER.

There is robust correlation between MAMs and lipid homeostasis. Since other organelles lack the capacity to synthesize phospholipids from their precursor, and the ER is a pivotal site for regulating cell intrinsic lipid balance, lipids must diffuse from the ER into other organelles. It has been previously reported that MAMs are a cholesterol enriched membrane system, predominantly composed of caveolin proteins, serving an essential function, contributing towards enriching the related elements of MAMs' lipid metabolism, thereby underscoring the indispensable role of MAMs in preserving lipid homeostasis. Phosphatidyl serines (PS), as the predominant enzyme system generated within the ER, is primarily localized on MAMs. Subsequently, it translocates to mitochondria to be converted into phosphatidyl ethanolamines (PE) (10). Some of the PE, upon return to the ER, transforms into phosphatidyl cholines, which is further distributed to various other organelles. In this process, the pro-phospholipid acid of PS is synthesized in the ER, but necessitates storage in MAMs.

In addition to phospholipid synthesis, MAMs also perform another crucial element of cholesterol metabolism. The newly synthesized cholesterol within the ER must be transported to mitochondria to convert into pregnenolone, the primary substance of sex steroids. In the rate-limiting step of this process, MAMs serve a pivotal role. Furthermore, research indicates the abundant presence of MAMs in cholesterol acyltransferase 1 (ACAT1), an enzyme responsible for the conversion of free cholesterol into cholesterol esters (CEs). Such CEs are commonly stored in fat droplets. Hence, it is feasible to indirectly evaluate the activity of MAMs by measuring the activity of ACAT1 (11). As such, MAMs have gradually emerged as the primary activator of mitochondrial steroid synthesis. Subsequently, MAMs also participate in the generation of ceramide, regulating cell growth, inflammation response, differentiation and apoptosis (12,13).

Significantly, it has been previously elucidated that MAMs are the initial locations of mitochondrial division (14). For instance, mitochondrial division proteins 1, mitochondrial division factors, and mitochondrial dynamics proteins are all sequestered at the MAMs site and completed prior to mitochondrial division (15). Additionally, processes such as mtDNA replication, mitochondrial transport and mitochondrial self-division, all revolve around the MAMs.

Mitochondrial fusion and division, a highly dynamic network system, maintains a steady state equilibrium of fusion and division under normal physiological conditions to ensure optimal cell functioning. Certainly, appropriate stimulation is paramount for maintaining a high quality of mitochondria. Among key constituents of the mitochondrial fusion mechanism, Mfn1, Mfn2 and optic atrophy 1 (OPA1) play pivotal roles. Notably, Mfn1, acting as a requisite GTPase for outer membrane fusion, primarily restricts mitochondrial function through its interaction with Mfn1 on the MAMs (16). In concert with Mfn1 and Mfn2 on the MAMs, Mfn2 helps form the mitochondrial outer membrane and acquires specific morphology (17). Given the heightened degree of Mfn2 enrichment on the MAMs, it is conjectured that the MAMs hold great significance during mitochondrial fusion, particularly when post-MITOL/MARCH5 ubiquitination machinery causes alterations in the intersection between the ER and mitochondria (18).

Acting as a cytosolic protein, Dlp1 dynamically congregates to the mitochondrial membrane and substantially enhances membrane contraction velocity via a GTP-dependent oligomerization pathway. Under hypoxic circumstances, the accumulation of the OMM protein FUNDC1 induces ectopic Dlp1 accumulation in the MAMs (19). Furthermore, as an integral component of the apoptotic process, Fis1 can bind to BAP31 in the MAMs, transmitting the mitochondrial apoptotic signals to the ER. BAP31, a critical escort protein on the ER membrane, participates in the degradation of misfolded protein and apoptotic signaling within the endoplasmic reticulum stress pathway. When Fis1 unites with BAP31, it cleaves BAP31 into p20 BAP31; as an apoptosis-promoting protein, p20 BAP31 activates procaspase-8 to convert it into a functional form, which can cleave Bid and initiate cell apoptosis (20,21). Activation of p20 BAP31 also facilitates Ca²⁺ translocation from the ER to the mitochondria, indicating the ability of cellular apoptotic signals to feedback to the mitochondria (22,23). The stability of calcium ions similarly directly or indirectly influences the dynamics of the mitochondria (24).

The relationship between calcium homeostasis and tissue structural integrity is exceedingly significant. With the excessive metabolism of Ca²⁺, it can induce the opening of the mitochondrial permeability transition pore, escalating the permeability of the inner mitochondrial membrane. The mitochondrion then undergoes depolarization, subsequently impeding ATP synthesis, leading to an expansion in the mitochondria's molecular form and ultimately causing the rupture of the outer membrane, thereby releasing a substantial amount of cytochrome c, culminating in apoptosis. Noteworthy, previous studies have also elucidated that apoptotic signaling exists within MAMs (25–27). The majority of apoptotic signals from the ER converge on the mitochondria autophagy pathway. This further suggests that the ER stress situation will directly influence the physiological alterations of the mitochondria, and the most pivotal factor among these is the BH3 protein (25), which is uniquely activated by the ER and transmits autophagy signaling to the mitochondria (26). However, presently, it remains elusive whether this protein can be concurrently activated by all forms of ER damage, or is activated only during specific pathological processes where the ER is specifically damaged. It is conceivable that it may emerge as a potential therapeutic drug target for diseases in the future (27).

Moreover, the mitochondrial division factor Fis1 aids in maintaining the junctions between the ER and mitochondria through its interaction with Bap31 (28). When procaspase-8 is recruited, the cleavage of Bap31 will lead to an increase in mitochondrial permeability and instigate apoptosis (29,30). In the ordinary state, ceramide is synthesized via the ceramide synthase pathway. However, under stress conditions (for example, heat shock, TNF-α, Fas, chemotherapy drugs, toxins, radiation and other factors), ceramide can be rapidly synthesized in sphingomyelinase from sphingomyelinase. The accumulation of ceramide not only modulates various molecules involved in apoptotic signaling transductions but can interact with them, such as protein phosphatase 1A/2A, protein kinase C, NF-κB and Ras. A substantial accumulation of ceramide can lead to the formation of pores on the external mitochondrial membrane, induce the release of pro-apoptotic substances (such as cytochrome C) in the mitochondrial membrane gap, and propagate stress signals from the ER to the mitochondria (31). Whereas suppressing the activity of ACS1/4 can reduce the synthesis of ceramide and deter the occurrence of cell apoptosis (32). Nevertheless, given the intricate nature and cross-domain relationships of apoptosis itself, markedly more profound and meticulous discussions are needed to delve deeper into this complex matter.

Research signifies that FUNDC1 is a ubiquitous protein within organisms (46). This protein is composed of 155 amino acids, encompassing three membrane spanning regions. Notably, its N terminus harbors the LTR motif, which aids in interaction with LC3 to regulate autophagy in mitochondria (41,42). The regulation of this activity is notably prominent under low oxygen environments; the study predominantly focused on the effects of decreased Src kinase activity and weaning tyrosine 18 phosphorylation levels, thereby reinforcing the mutual interplay between LC3 and FUNDC1 (46).

FUNDC1 can also play a pivotal role in calcium transfer through interaction with IP3R2. Under hyperglycemic conditions, the activation of FUNDC1 can stimulate the binding of CREB to the FIS1 promoter, thereby promoting MAM formation. This indicates that FUNDC1 plays a critical part in the entire process of MAM formation. Additionally, FUNDC1 also participates in regulating mitochondrial dynamics, forming a synergistic relationship with OPA1. It has been discovered that incorporating change in lysine 10 in FUNDC1 significantly induces mitochondrial aggregation, reflecting the importance of FUNDC1 in regulating mitochondrial dynamics (47). NRF1, as a transcription factor, can stimulate its expression by binding to the FUNDC1 promoter 186/176 (48).

In HeLa cells, experiments have revealed that suppressing expression of FUNDC1 propels mitochondrial fusion, whereas augmenting its expression retards it, probably by inducing DRP1 to drive mitochondrial proliferation (49). This process also encompasses phosphorylation at site S13, which attenuates the interplay between FUNDC1 and Drp1 while amplifying the interaction with OPA1. These observations signify that alterations in FUNDC1 structure may guide distinct pathways that culminate in corresponding alterations in mitochondrial structure. Research along the path of FUNDC1 upstream regulation and its influence on structural alteration is projected to be a vital direction of future studies. Within the unique structure of MAMs, FUNDC1 plays a pivotal role in the evolution of various pathologies.

Experimental evidence has confirmed that suppression of FUNDC1 expression fosters the generation of extensive MAMs in diabetes-induced cardiomyopathy. This morphological and functional reconfiguration of MAMs initiates cell apoptosis and the disintegration of abnormal mitochondria, ultimately resulting in reduced synthesis and disruption of the respiratory chain function of mitochondria. In both patients afflicted with heart failure and murine cardiac muscle cells, a decrease was observed in the FUNDC1 protein level (49). Additional research uncovered that FUNDC1 mainly impairs mitochondrial function, causing harm to cardiac muscle cells, and the disruption of MAMs is intricately linked to mitochondrial dysfunction (50). Similarly, magnesium oxide and α-lipoic acid can diminish the phenotypic characteristics of cardiac muscle cells through interaction with FUNDC1 (51). Besides these diseases, FUNDC1 can also instigate mitochondrial autophagy, promptly triggering cell apoptosis and myocardial infarction (52). These instances not only underscore the significance of FUNDC1 but also spotlight the pivotal position of MAMs within cellular processes.

The PACS family is composed of the two proteins PACS-1 and PACS-2, which share a similar structure but exhibit distinct functions. Both proteins contain a furin binding region (FBR), an intrinsically disordered mid-region (MR), and a C-terminal region (CTR) (52). Specifically, the MR domain encompasses a native nuclear localization signal (NLS) domain and an Akt phosphorylation site, although the precise function of the CTR domain remains undefined (53). The prevailing consensus in academia suggests that the FBR domain plays a crucial role in recognizing and adhering to cargo proteins.

In 1998, Werneburg et al (54) identified the crucial role of PACS-1 in directing trafficking across the Golgi network (TGN) for the first time. Subsequently, in 2005, Köttgen et al (55) postulated that both PACS-1 and PACS-2 were involved in the transport process of polycystin-2 mediated by members of the TRP ion channel family (TRPP2). PACS-2 can precisely identify and bind cargo proteins with acidic ionization clusters, facilitating their transportation towards relevant organelles and thereby influencing cellular activities ranging from calcium exchange and apoptosis to membrane transport (56).

Numerous studies suggested that PACS-2 influences immune-induced apoptosis by regulating MAMs and thereby altering mitochondrial division. Additionally, PACS-2 binds to CNX in the cytoplasm and regulates the distribution of CNX to MAMs (57). Moreover, PACS-2 can interact with BIM, inviting the recruitment of BIM to lysosomes in a mitogen-activated protein kinase-JNK-dependent manner to form the apoptosis complex (58). Deeper research indicates that interaction of PACS-2 with ataxia telangiectasia mutated (ATMs) can activate NF-κB to promote cell survival (59). Furthermore, previous evidence demonstrated that PACS-2 participates in DNA damage-related apoptosis through two independent mechanisms. Firstly, following DNA damage, PACS-2 employs its NLS domain to shuttle itself into the nucleus and interact with SIRT1, thus hindering the deacetylation of p53, leading to cell cycle arrest (60). Secondly, upon DNA damage, PACS-2 engages ATM to activate NF-κB, promoting the expression of the anti-apoptotic protein Bcl-xL (61). Factors such as TRAIL can induce dephosphorylation of PACS-2 at Ser437 indirectly via Akt, thereby stimulating mitochondrial membrane permeability increase and lysosomal membrane permeability increase (62). By contrast, the stable phosphorylation of PACS-2 is synchronous with the p53/p21 and NF-κB/Bcl-xL pathways, serving as a cytoprotective mechanism.

Initially recognized as an obligatory dynein-like protein integral to outer membrane fusion, Mfn2 has recently been revealed to be localized on the ER membrane, engaging in reciprocal interactions with the OMM. Research indicated that the expression of Mfn2 alters the MAM hierarchy and is capable of enhancing the ER-mitochondria distance within the cell (63), hinting that it plays a pivotal role in sustaining mitochondrial morphology and ER-mitochondria contact sites interconnection. Nevertheless, existing findings pose contradictions to this hypothesis, revealing that cells with Mfn2 variations or deprivation may actually enhance ER-mitochondria coupling (64,65), suggesting an imperative for further investigation into the precise impact of Mfn2 on the MAM.

Significantly, Mfn2 serves as a receptor during the PINK1-Parkin-mediated autophagy process, playing a critical role in interface management (66). Moreover, Mfn2 directly interacts with the mitochondrial transport machinery, encompassing MIRO1/2 transmembrane transporters, specifically linked to the function of MARC proteins (67). Mfn2 has been proven to influence the fatty acid metabolism of mitochondria by binding mitochondrial with lipid particles (68) and facilitating the transfer of phosphatidylserine from the ER to the mitochondria.

The downstream repercussions of Mfn2 on mitochondrial functionality are manifold, including alterations in the mitochondrial ultrastructure, cristae and supramolecular structures, affecting the oxidative phosphorylation process (69,70). Furthermore, the MAM can also regulate the oxidative phosphorylation process through calcium ion signal transmission (71). Mfn2 is also implicated in modulations of mtDNA stability, potentially due to its fusion effect leading to decreased mtDNA copies and increased mtDNA deletion frequency (72) which is pivotal for the distribution of mitochondrial DNA proteins. Additionally, studies have highlighted the crucial role of Mfn2 in preserving podocyte apoptosis through regulating the PERK pathway (73). Therefore, the multifaceted functions of Mfn2 contribute to explaining why cells lacking Mfn2 display diminished mitochondrial respiration.

Despite the diverse proteins existing on MAMs, the functional studies of Mfn2, FUNDC1 and PACS-2 are more comprehensive. Moreover, the influence of these proteins on related diseases is more profound. In addition to these pivotal proteins, MAMs also harbor critical participants including DJ-1, TDP-43 and CypD, although they do not directly affect MAM structure but play a crucial regulatory role in specific MAM functions. IP3R is an important Ca²⁺ efflux channel located at the ER surface, which mediates the release of Ca²⁺ from the ER lumen to the cytoplasm (74). VDAC is an ion channel located at the outer mitochondrial membrane; it mediates the movement of various ions and metabolites into and out of mitochondria and is involved in a series of cellular activities, including cell apoptosis, metabolism and regulation of Ca²⁺ (75). IP3R and VDAC are linked by Grp75 to maintain MAM structure (76). It is known that overexpression of VDAC can enhance the connection between ER and mitochondria, thereby improving the flux of Ca²⁺ from the ER to the mitochondria (77); when silencing VDAC1, the connection between Grp75 and IP3R1 decreases, suggesting decreased ER-mitochondrial interaction (78). Cells overexpressing Grp75 exhibit more IP3R1-VDAC1 interaction sites (79). Silence of IP3R1 or Grp75 can also reduce the connection between VDAC1 and Grp75 or IP3R1 (80).

Moreover, VAPB located within the ER membrane, participates in the activation of IRE1/XBP1 axis during the unfolded protein response in the ER (81,82). VAPB can form a complex with the outer mitochondrial membrane protein PTPIP51 and help maintain the structure of MAM. The mutant form of VAPBP56S, showing stronger affinity for PTPIP51, thereby promotes the transfer of Ca²⁺ from the ER to the mitochondria; knocking out any one of these two genes can reduce the transfer signal of Ca²⁺ (83) and decrease the level of contact between the ER and the mitochondria (84,85).

MOSPD2 is another member of the VAP family; it is a protein located on the surface of the ER membrane which can connect the ER and other membrane structures, and can also bind to small proteins that interact with VAP through the MSP (major sperm protein structural domain), a protein sequence motif called FFAT, such as PTPIP51 on the outer mitochondrial membrane (86). REEP1 is a protein located on the ER and the outer mitochondrial membrane. It has been demonstrated that REEP1 directly connects the ER and mitochondria through oligomerization and is involved in the formation of the MAM structure. Furthermore, REEP1 bends the ER membrane so that the ER can wrap around the mitochondria, which helps form MAMs (86). The complexity they participate in further highlights the complexity of MAMs, prompting to conduct more in-depth exploration (Table I) (Fig. 1).

Mitochondria are organelles involved in cellular energy production and biosynthetic processes (91). Both their content of mtDNA and expression levels of relevant mitochondrial mRNAs are altered during tumor progression, including the development of ovarian cancer. Investigations have suggested that suppressing mitochondrial autophagy may effectively mitigate the disease progression of cisplatin-resistant ovarian cancer (92,93). The studies by Yu et al (96) demonstrated that inducing mutations in the p62 UBA structural domain could regulate subcellular localization of HK2 in A2780 ovarian cancer cells' mitochondria, freeing PINK1/parkin-mediated mitochondrial autophagy to decrease cell sensitivity to cisplatin. Similarly, Vianello et al (94) observed an increase in the content of the mitochondrial autophagy receptor BNIP3 in cisplatin-resistant cells and in ovarian cancers resistant to platinum chemotherapy. Additionally, Zhou et al (95) revealed that the potent potential of a complex of glycosylated zinc (II)-cryptolepine could disrupt the mitochondrial autophagy pathway and induce autophagy and apoptosis in SKOV-3/DDP cells, highlighting its capability in developing chemotherapeutic drugs against cisplatin-resistant SKOV-3/DDP cells. Simultaneously, Yu et al (96) confirmed that ABT737, a potent inhibitor of BCL2/BCLXL, could considerably elevate the concentration of DRP1 in mitochondria, thus triggering the release of Cytochrome C in mitochondria and their autophagy in SKOV3/DDP cells. This finding underscores the suitability of targeting antiapoptotic proteins of the BCL2 family as a novel therapeutic strategy for treating patients with ovarian cancer with cisplatin resistance.

Inducing mitochondrial autophagy may trigger the process of programmed cell death in ovarian cancer cells at the terminal stage. Chen et al (97) discovered that the antimicrobial peptide pardaxin can stimulate PA-1 and SKOV3 cells to generate excessive ROS. This surplus ROS accomplishes this by decreasing the destruction of fusion proteins, declining the expression of mitochondrial transporters 1/2 and L-/S-OPA1, inducing the expression of fusion proteins DRP1 and FIS1 to enhance mitochondrial fission rates, and at the same time initiating the expression of autophagy-related proteins Beclin, p62 and LC3 to stimulate the apoptotic pathway. Furthermore, Wang et al (98) revealed that the epoxidecolchicine H derived from the metabolism of Phomopsis was capable of effectively increasing the ROS levels in cells, weakening the mitochondrial membrane potential, thereby causing damage to mitochondria, activating the mitochondrial autophagy process. Concurrently, this compound is also able to mediate apoptosis pathways associated with ER stress, further propelling the apoptotic process of ovarian cancer A2780 cells (98). Katreddy et al (99) study identified that high malignant epidermal growth factor receptors (EGFR) are frequently overexpressed in solid tumors. The use of siRNA or synthetic EGFR downregulating peptides (Herdegradin) can effectively downregulate the expression of EGFR protein. Notably, this downregulation is achieved by activating the mTORC2/Akt pathway, stimulating selective mitochondrial autophagy, and achieving the selective elimination of ovarian cancer cells (100).

Moderate suppression of mitochondrial autophagy may restrain the tumor's metastatic capacity. Yuan et al (101) indicated that mice exposed to BPA/BPS are more susceptible to tumor metastasis, as BPA/BPS can enhance the stem cell characteristics of ovarian cancer cells via a non-normal PINK1/p53 mitochondrial autophagy process, and the moderate suppression of mitochondrial autophagy can restrain this augmentation effect.

Focusing on the mitochondrial autophagy, researchers aim to elucidate novel targeted targets in ovarian cancer therapy. Martinez-Outschoorn et al (102) have elucidated that BRCA1 tumor suppressor gene deletion can instigate hydrogen peroxide production, wherein the hydrogen peroxide produced by BRCA1-null ovarian cancer cells stimulates NFB activation in stromal fibroblasts, inducing oxidative stress and consequently triggering mitochondrial autophagy and catabolic processes. Concurrently, MCT4 marker upregulation and Cav-1 expression loss also occur. Jin et al (103) further discovered that fucosylation of TGF-β1 augments Trk-like autophosphorylation via the PI3K/Akt and Ras-Raf-MEK-ERK pathways, thereby enabling ovarian cancer cell regulatory functions. This provides an alternate research avenue for TGF-β1 targeting in ovarian cancer therapy. Bae et al (104) identified that campesterol influences mitochondrial function, triggering excessive calcium accumulation and the creation of ROS, thereby inflicting ER stress and thereby inhibiting ovarian cancer. They observed in experimental settings that campesterol amplified the efficacy of conventional anticancer drugs, presenting potential as a novel drug for future treatment of ovarian cancer; however, this enhanced anticancer effect requires further study.

In summary, mitochondrial autophagy plays a substantial role in ovarian cancer therapy. It not only enhances the sensitivity of ovarian cancer cells to chemotherapy drugs and reduces drug resistance by inhibiting mitochondrial autophagy; but also triggers mitochondrial autophagy to drive ovarian cancer cell apoptosis. Moreover, manipulating mitochondrial dynamics, enhancing mitochondrial autophagy, or prodigiously initiating ROS generation and suppressing mitochondrial autophagy can ultimately lead to ovarian cancer cell demise. Hence, regulating the mechanisms of mitochondrial autophagy may be conjectured as a potential strategy for ovarian cancer therapy.

Based on the presence or absence of ribosomes at the cisternal face of cell membranes, ER can be classified as RER and SER. These constitute distinct spatial domains that are nevertheless integrally related constructs (105). Moreover, the ER can also be classified based on its membrane structure features. These structures encompass the outer nuclear membrane, flared ER pools, and a polygonal pipeline system composed of triangular junction rings (106).

The ER lies in proximity to numerous other organelles and boasts extensive volumes within cells, the magnitude of which is contingent upon the type of cell. Notably, the interaction with mitochondria merits special mention. Given the pivotal role of mitochondria in organs (specifically their function during apoptosis), this association assumes paramount importance (107,108). In fact, this connection between the ER and mitochondria is predominantly mediated by the MAM (109). Additionally, MAM synergizes with the cell membrane to maintain its stability and growth. This interplay is controlled by Ca²⁺ levels and several proteins, including stromal interaction molecule 1 located in the ER and calcium release-activated calcium channel protein1 residing in the cell membrane (110). Notably, the ER appears to also partake in autophagy processes, as observed by linking endocytic vesicle systems (111). When contacted with specific ER assemblies known as sub-Golgi bodies, one of the core structures of autophagosomes-the phagophore will proliferate and mature into a mature autophagosome (112,113).

Recent scientific literature from recent years suggests that ER stress can significantly diminish the resistance of ovarian cancer cells. Cheng et al (114) discovered in their research that mitochondrial protease OMA1 not only triggers the morphogenesis of mitochondrial structures by cleaving OPA1 but also significantly reduces the drug resistance of ovarian cancer cells by integrating ER stress through its interaction with the PHB2/OMA1/DELE1 pathway. Additionally, Jung et al (115) identified that DPP23, functioning as an initiator of ER stress, effectively combats ovarian cancer resistance. Xu et al (116) revealed that PHLDA1 fine-tunes the apoptotic sensitivity of ovarian cancer cells via the ER stress response process. Kim and Lee (117) corroborated that 6-gingerol induces ER stress in ovarian cancer cells and successfully overcomes resistance to gefitinib, thus providing a novel strategy for treating ovarian cancer using the combination of gefitinib and 6-gingerol. Lastly, Bahar et al (118) suggested that the combination of PARPis and cis-diminution of cis-OC cells may present an efficacious method to broaden therapeutic potential in response to ER stress, thereby overcoming platinum chemotherapy resistance in OC and PARPi cross-resistance.

ER stress is progressively emerging as a novel treatment approach for ovarian cancer (119). Rezghi et al (120) demonstrated using experimental evidence that miR-3c-1-1p regulates XBP30/CHOP/BIM-mediated ER stress, suppresses transcription of XBP2 in ovarian cancer cells and consequently triggers the activation of the apoptosis pathway. Kong et al (121) utilized platinum (IV) prodrug and near infrared II (NIR II) photothermal agent IR1048 as the foundation, generating enhanced ER stress through formation of reduced-sensitive polymer nanoparticles to amplify therapeutic effects against ovarian cancer. Wang et al (122) found that during their research, Erythropoietinaxin 2A9 (EpoxiDRESSIN H), was capable of triggering apoptosis pathways related to mitochondria and ER stress, thereby stimulating apoptosis of human ovarian cancer A2780 cells further. Similarly, Wang et al (123) reported that DWP05195 could induce ER stress via the ROS-p38-CHOP pathway in human ovarian cancer cells, triggering cell apoptosis. Yart et al (124) discovered that activation of UPR by cellular fusions increases the generation of polyploid multi-cancer cells in vitro and bestows them with new attributes, and also established that regulation of UPR in patients with ovarian cancer could represent an intriguing and potent therapeutic strategy. Chen et al (125) efficiently suppressed proliferation and migration of prostate specific membrane antigen (PSMA)-positive cells by inhibiting ENTPD5 and at the same time, blocked the activation of GRP78/p-eIF-2α/CHOP pathway, providing potential effective therapeutic targets for investigating prostate cancer treatment. Barez et al (126) confirmed in the context of studying IRE1a inhibitor STF-083010 that suppressing caspases-12/3 and Bax/Bcl-2 proteins could effectively inhibit ovarian cancer proliferation, revealing STF-083010 as a novel potential therapeutic target for treating ovarian cancer cells associated with ER stress. Moreover, in addition to IRE1a inhibitors, Zundell et al (127) posited that IRE1a/XBP1 pathway carries innovative therapeutic potential against ARID1A-mutated ovarian cancers, providing scientific basis for drugs concurrently utilizing the IRE1a/XBP1 pathway. Ma et al (128) identified that under low glucose and metformin's effect, ANGII triggers inhibited ER stress, inducing the formation and migration of ovarian cancer spheroids. By contrast, Lin et al (129) found that this pathway had comparable effects on ovarian cancer cells expressing CARM1 and could achieve the therapeutic objective by decreasing overexpressed CARM1. Additionally, Xiao et al (130) used WEE1 inhibitor AZD1775 to stimulate PERK, thereby triggering apoptosis of ovarian cancer cells, and in clinical practice, combined AZD1775 with IRE1α inhibitor MKC8866 to achieve synergistic anti-ovarian cancer effects. Zhang et al (131) observed that ANGII regulates lipid desaturation, triggering suppression of ER stress, resulting in the formation and migration of ovarian cancer spheroids.

Singla et al (132) asserted that naturally occurring compounds play a pivotal role in regulating ER stress, further demonstrating that various such natural substances, such as quercetin, curcumin and resveratrol, exhibit effective ER stress inhibitor effects in the context of ovarian cancer. Hong et al (133) employed the action of mountain heteroflavone complex extracted from tricuspid fruit on ovarian cancer cells, observing apoptosis of cancer cells; subsequent studies revealed that mountain heteroflavone can interfere with mitochondrial co-localization through inhibiting the PI3K/AKT and MAPK pathways and initiate ER stress. Li et al (134) identified cucurbitacin I as inducing death of ovarian cancer cells via the ER stress pathway. Bae et al (135) discovered that fucosterol (present in algae) could induce mitochondrial dysfunction and ER stress, thereby suppressing the proliferation of ovarian cancer cells. Zhu et al (136) elucidated that naringin could regulate the PI3K/AKT/mTOR signaling pathway to suppress SKOV3/DDP cell autophagy, and also facilitate SKOV3/DDP cell apoptosis by targeting ER stress; these two mechanisms synergistically counteract tolerance to cisplatin exhibited by SKOV3/DDP cells. This experimental outcome strongly supports the extensive application prospects of natural compounds in treating ovarian cancer therapies (137). Bae et al (138) discerned the regulatory effect of fucosanglioside in maqueigao (Centricellularis longicaudata), a natural compound, on ER stress to restrain the proliferation of ovarian cancer cells. Kim and Ko (139) also posited that JIO17 from traditional Chinese medicine can induce ovarian cancer cell apoptosis through the NOX4/PERK/CHOP pathway.

Abdullah et al (140) investigated the mechanism by which ER stress induces release and binding of calreticulin in ovarian cancer cells, hypothesizing that calreticulin has a profound connection with immunogenic cell death in ovarian cancer cells; meanwhile, existing experiments have confirmed the value of calreticulin in prognostic evaluation and prediction (141), and future research remains necessary. Bi et al (142) triggered immunogenic cell death in ovarian cancer through initiating ER stress using a mitochondrial uncoupling agent benzylamine, and remarkably inhibited tumor progression. Separately, Lau et al (143) discovered that paclitaxel triggers generation of ER stress through the TLR4/IKK2/SNARE pathway, leading to immunogenic cell death in ovarian cancer cells, suggesting a higher occurrence rate of immunogenic cell death in ovarian cancer and therefore possessing significant research significance; the importance of CALR as a crucial indicator for paclitaxel chemotherapy in ovarian cancer was also underscored.

Beyond addressing mortality, the immune system also plays a significant role in tumor cells (144,145). For instance, Song et al (145) discovered that ER stress IRE1a/XBP1 potentially influences T cell metabolic adaptability and antitumor potency, thereby influencing the antitumor immunity of patients with ovarian cancer, providing a novel therapeutic approach in immunotherapy. Furthermore, Cao et al (146) elucidated the central function of Chop in tumor-induced dysfunction of CD8 T cells, and the potential for therapeutic efficacy to release T cell-mediated antitumor immunity through blocking Chop or ER stress.