Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways

Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways Dejian Chen, Shuo Zhang, Shuhao Sheng, Lingshi Cai, Jisuo Zheng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3704046/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Exercise, as an effective non-drug intervention, plays an important role in preventing and alleviating several diseases. Endoplasmic reticulum (ER) stress is caused by an excessive accumulation of unfolded or misfolded proteins in the ER and also serves as the body’s internal self-protection mechanism. ER stress occurrence can be detected in the cells in many diseases such as cancer, diabetes, obesity, osteoporosis, neurodegenerative diseases, and metabolic diseases. In recent years, exercise has been suggested to change the molecular mechanisms related to various diseases by regulating ER stress. With increasing attention on women's health, some common diseases have also become research hotspots, such as breast, ovarian, cervical, endometrial cancer, polycystic ovary syndrome (PCOS) and endometriosis prevention and treatment; and other diseases. This manuscript reviews the relationship between exercise and ER stress and its role in common female endocrine system-related diseases. Exercise ER stress Breast cancer Ovarian cancer Cervical carcinoma Polycystic ovary syndrome Figures Figure 1 Figure 2 INTRODUCTION With an improvement in the living standards and newfound health consciousness, an increasing number of people are devoting themselves to physical exercise, ranging from the "square dance" loved by middle-aged and older people to the "Wechat step ranking" used regularly by young individuals. Exercise has become a part of people's lives. In China, August 8 has been celebrated as "National Fitness Day" since 2009. Exercise is essential for health and fitness, not only to improve immunity, cardiovascular function, and metabolism [1] but also from a cellular and molecular point of view since long-term exercise training can regulate ER stress and mitochondrial function and prevent apoptosis [2-4]. Currently, the incidence trend for cancer is increasing in younger adults. Breast, cervical, and ovarian cancers are still the most common causes of malignant tumor-related deaths in women. The World Health Organization currently advocates that countries strive for the following goals: > 90% coverage of human papillomavirus (HPV) vaccination of girls younger than 15 years; > 70% coverage of effective cervical carcinoma screening of adult women aged 35-45 years; and ensuring the acceptance of rational treatment and management by at least 90% of women with lesions, post-screening. As a non-invasive and economical health promotional tool, research to elucidate the role of exercise in common female diseases and related molecular mechanisms will provide a theoretical basis for the clinical treatment of women's health. The effects of post-exercise-induced changes in the ER in several diseases have received increasing attention from researchers. The relationship between exercise and ER stress and the effect of exercise-regulated ER stress on the disease is a hot topic of research in the field of exercise and health and biomedicine. Numerous studies have shown that exercise can effectively ameliorate various ER stress-related disorders, including obesity, type 2 diabetes, cancer, neurodegeneration, osteoporosis, and sarcopenia, through different mechanisms [5-8]. The molecular mechanisms linking exercise regulation of ER stress to the development of some diseases still need to be actively explored. Exercise and ER stress 1.1 Occurrence of ER stress The ER is an important organelle for the translation, synthesis, folding, and transport of protein and the storage of intracellular calcium ions in eukaryotic cells. The stability of the internal environment of the ER is essential for the realization of ER function, and therefore, homeostasis in the ER is highly maintained. Several stimuli, including ischemia-reperfusion injury, oxidative stress, metabolic intermediates such as homocysteine, excessive intracellular protein synthesis exceeding protein folding capacity, disorders of calcium metabolism in the ER, impaired lecithin synthesis, and several other physical, chemical, or genetic factors can trigger the ER stress, which, in turn, triggers the unfolded protein response (UPR). The UPR is mediated by an ER molecular chaperone, glucose-regulated protein 78/binding immunoglobulin protein (GRP78/BIP), and three ER stress transmembrane proteins [9, 10]. These three proteins are the double-stranded RNA (dsRNA)-dependent protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF-6), and inositol-requiring enzyme 1 (IRE-1). Under normal physiological conditions, the amino terminus of these three transmembrane proteins, PERK, ATF-6, and IRE-1, are bound to GRP78/BIP in an inactive state. When ER stress occurs, GRP78/BIP dissociates from these three proteins and binds to unfolded proteins. In contrast, dissociated stress proteins are activated and reduce the accumulation of misfolded or unfolded proteins in the ER by initiating the respective UPR pathway. UPR is an adaptive response of cells that prevents cell death by removing misfolded proteins. However, in cases of unresolved stress, strong and persistent stimuli, and irreparable perturbances in the internal environment, the corresponding mechanisms are activated to induce apoptosis [11, 12]. Current research focuses on three main pathways. The first is the nuclear transcription factor CHOP (C/EBP homologous protein) pathway, which is the main pathway for ER stress to regulate apoptosis. When cells receive stimulation signals, CHOP, which is originally very low in content, starts to accumulate in large amounts and move from the cytoplasm to the nucleus. The downstream regulatory pathways of CHOP for apoptosis induction are through the following: i) mitochondria-dependent pathways, ii) death receptor pathway, and iii) other pathways, such as CHOP-ERO1α, CHOP-CaMKII, PERK/eIF2α/CHOP, CHOP-P21, Bag5-CHOP, and CHOP-FOXO3A pathways [13-15]. The second pathway is the JNK (c-Jun N-terminal kinase) pathway, which results from the sustained activation of IRE1 due to increased insulin synthesis, which, in turn, activates JNK by recruiting tumor necrosis factor receptor (TNFR) and apoptosis signal-regulating kinase 1 (ASK-1) to form the IRE1-TNFR-ASK1 complex, which activates JNK in cascade and induces β-cell apoptosis. The third pathway is the caspase-12-activated apoptotic pathway. The vital organs of the body are defended and protected through these above apoptotic pathways. 1Exercise regulates ER stress Studies have shown that different exercise programs can prevent and treat different conditions. Endurance training improves cardiovascular function [16], strength training reduces muscular dystrophy [17], and the combination of both training methods is beneficial for patients with type 2 diabetes [18]. Aerobic exercise is another positive approach to reducing plasma lipid abnormalities and improving the prognosis of cardiovascular disease [19]. However, there are no clear conclusions on the effects of different exercise modalities, exercise intensity, and exercise duration on the ER stress intensity, stress duration, and effects in different organs and tissues. Studies have shown that long-term exercise can slow down ER stress and reduce insulin resistance. The IRE1-JNK pathway is the classical signaling pathway of ER stress that triggers insulin resistance, and numerous studies have now shown that long-term endurance exercise can alleviate the symptoms of type 2 diabetes, reduce blood glucose levels in the body, and improve the sensitivity of insulin receptor [20]. Exercise training in adolescents with type 2 diabetes significantly improved the expression levels of the blood ER stress related protein GRP78 by both low-intensity and high-intensity intermittent exercise [21]. It was found that rats trained at high intensity for 5 weeks experienced ER stress and significantly reduced expression of apoptosis-signaling proteins CHOP and ATF4 in the skeletal muscle compared to rats in the low-intensity and no-exercise groups [22]. In a 6-week endurance treadmill training exercise in the GK rats, which did not affect hepatic ER stress and the hepatic insulin signaling pathway in rats [23]. However, it improved the blood glucose levels in the GK rats and was beneficial in maintaining the steady-state amount of blood glucose levels, indicating that perhaps 6 weeks of endurance treadmill training was insufficient to reduce the expression of BIP and IRE1. Aerobic exercise is known to reduce the signature UPR protein induced by myocardial infarction and improve cardiac function in rats. However, short-term aerobic exercise is also insufficient to induce increased expression of myocardial protein GRP78 and CHOP [24, 25]. It was also reported that endurance exercise training also only mildly increased the expression of GRP78 in skeletal muscle [26]. The presence of ER stress in the prefrontal lobe of SD rats fed a high-fat diet to induce obesity and speculated that excess ER stress may play a key role in reducing the levels of neuroplasticity-related proteins [27]. However, aerobic exercise significantly reversed the expression of GRP78, p-PERK, p- eukaryotic initiation factor-2α (eIF2α), caspase-12, CHOP, and Bax/Bcl-2 in the prefrontal cortex of SD rats with obesity. After 3 weeks of high-intensity treadmill training of obese mice on a high-fat diet, the hypothalamus showed maximal ER stress but no apoptosis [22]. Collectively, the intensity of exercise, rather than its volume or duration, may play a critical role in magnifying the protective effect of exercise against nonalcoholic fatty liver disease [28]. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a co-transcription factor that is abundantly expressed in tissues that are active in energy metabolism, such as the cardiac muscle, skeletal muscle, brown fat, and brain. Exercise has been shown to increase PGC-1α levels in the skeletal muscle, initiating the downstream factor fibronectin type III domain-containing protein (FNDC) 5 to promote fat thermogenesis by acting on peroxisome proliferator-activated receptor alpha (PPARα). Meanwhile, PPARα also increases the expression of uncoupling protein 1, activates brown fat-associated groups, and accelerates the browning of white fat to achieve weight loss [29, 30]. In PGC-1α knockout mice experiments. It was found that by knocking out CHOP and thus blocking apoptosis in the ER stress related pathway, ATF6 α-knockout mice could not recover from acute exercise on their own but could improve exercise intolerance [31]. 3-month aerobic exercise training resulted in decreased expression levels of ER stress related proteins, such as GRP78, p-IRE1, and p-eIF2α, in the subcutaneous adipose tissue and peripheral blood mononuclear cells of obese individuals [32]. Reduced expression levels of both ER stress related proteins p-PERK and CHOP were also found in experiments combining intermittent stair-climbing training and reduced caloric intake [33]. Moderate exercise initially causes activation of the ER stress and UPR pathways, probably due to adaptation mechanisms in the skeletal muscle. However, after multiple training sessions, the ER stress and UPR-related signaling molecules, including BIP, GRP94, GADD34, and ATF4, are reduced [34]. Currently, more studies focus on the ER stress response of strength training-induced skeletal muscle [35]. However, in terms of the studies on adipose tissue, although diverse, the exercise forms are mainly aerobic; few studies have studied resistance training in the context of ER stress state and the inflammatory response in adipose tissue. Overall, moderate intensity and duration of exercise are holistic in their stimulatory effect and have protective and favorable effects on neurological, cardiovascular, and motor system diseases. The beneficial role of exercise in the following diseases by regulating ER stress pathways 2.1 Breast cancer Breast cancer (BC) has become a common malignancy threatening women's health physically and mentally, and is prone to postoperative recurrence, with a high rate of malignant metastasis and an increasing incidence in younger adults [36]. Substantial evidence has revealed the effect of lifestyle and environmental factors on the development of BC, such as a high-fat diet, alcohol consumption, and lack of physical activity. The elimination of BC (primary prevention) may reduce morbidity and mortality. Secondary prevention, including diagnostic tests (e.g., mammography, ultrasonography, magnetic resonance imaging, molybdenum target mammography, breast self-examination, etc.), helps in the early detection of tumor-prone lesions [37, 38]. Although the postoperative 5-year survival rate of early BC can reach 80% [39], the postoperative distant recurrence and lung metastases adversely affect the overall survival rate for BC. Therefore, there is a need to further explore the signature oncogenes in BC cell growth and metastasis and to reveal their regulatory mechanisms in BC development. One study found accelerated tumor growth and metastasis in mice after they were made to consume alcohol; in vitro, alcohol treatment significantly promoted BC cell proliferation and migration [40]. Alcohol chronic treatment induced a rise in the expression of reactive oxygen species (ROS) and ER stress activation protein p-eIF2a, BIP, and X-box binding protein 1 (XBP1)-s, and the reversal effect of 4-phenylbutyric acid (4-PBA) was observed on ethanol-induced chronic stress by pretreating E0771 cells, a murine BC cell line, with 4-PBA before ethanol treatment. Alcohol consumption is suggested to promote the malignant progression of BC cells through the induction of ER stress. ER stress inducer, tunicamycin, is a nucleotide antibiotic produced by actinomycetes. The mRNA and protein levels of ER stress-responsive genes (IRE1α and BIP) were upregulated in breast cancer cells [41]. The results showed that ER stress induced apoptosis in MDA-MB-231 by upregulating the expression of PERK, eIF2α, ATF4, CHOP, and caspase 4 that calpain could be a potential target for BC therapy [42]. A recent study [43] found that GRP78 was located intracellularly and not on the cell surface of the human BC cells MDA-MB-231 or it is secreted in the conditioned media. However, there is still a need to explore the signature oncogenes in BC cell growth and metastasis and to reveal their regulatory mechanisms in BC occurrence and development. Tripartite motif family protein (TRIM) 25 as a novel ER stress inducible protein that regulates the survival of BC cells by participating in ER stress induced apoptosis [44]. Recent research reports that combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy [45]. There is a study revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during BC tumor metastasis [46]. P38-mediated induction of ER stress response is autophagy in human breast cancer cells. Activation of endoplasmic reticulum stress mediated pathway is an important cause of apoptosis of breast cancer cells. [47, 48]. Presently, studies on the effect of exercise on ER stress in BC are scarce. In a study of exercise combined with berberine administration, changes in the expression of downstream apoptosis-related proteins induced by the mitochondrial pathway, Fas-mediated death receptor pathway, and ER stress pathway were suggested to be the mechanism by which exercise co-operates with berberine to delay breast tumor growth [49]. Exercise as an adjunct is thought to protect against cancer development and metastasis by reducing hormonal stimulation in hormone-dependent cancers or by decreasing the permeability of the blood vessel wall to the invading metastatic cells. Exercise training increased circulating estrogen levels in the rat model of ovarian cancer, but the exact mechanism is not fully understood. The ER plays an important role in processes such as protein folding for hormone synthesis. Therefore, additional studies are necessary to address the potential protective vascular changes involved in exercise training-modulated anti-metastatic effects of ER stress in BC [50]. As ER stress induced apoptosis in tumor cells is gradually gaining momentum in research, revealing novel regulatory mechanisms between the ER stress related proteins and pathways and BC can provide new ideas and theoretical support for the early diagnosis and clinical treatment of BC in the future. 2.2 Ovarian cancer Ovarian cancer (OvCa) is also one of the common gynecologic malignancies and can occur at any age. Owing to the lack of reliable screening tests and the ambiguous symptoms, ovarian malignancies are not easily detected in early-stage lesions and lack effective treatment in advanced cases; consequently, their morbidity and mortality rates rank the topmost in gynecologic malignancies [51]. Currently, OvCa clinical treatment is mainly based on chemotherapy, although chemotherapeutic drugs have disadvantages such as causing severe adverse reactions, unclear targeting, and prone to developing drug resistance [52]. Therefore, finding efficient and targeted treatments for OvCa is an urgent problem, and studying the molecular pathogenesis of OvCa is of utmost importance for the treatment of OvCa. Studies have shown that ER stress may play an important role in the anticancer activity of proteasome inhibitors. ER stress-related genes are vital factors predicting the prognosis of OvCa, and possess great application potential in the clinic [53, 54]. Some scholars observed the effect of proteasome inhibitor MG132 on OvCa cell line SKOV3 in vitro , and found that MG132 induced ER stress in SKOV3 cells, and the CHOP gene-mediated ER stress apoptotic pathway played an important role in the anti-OvCa activity of MG132 [55]. There was a study demonstrated that ENTPD5 knockdown inhibited SOC cell proliferation, migration and restrained the activation of the GRP78/p-eIF-2α/CHOP pathway, which provides a potentially effective therapeutic target for the treatment of OvCa [56]. In contrast, when SKOV3 cells were treated with the inositol 1,4,5-triphosphate inhibitor, 2-aminoethyl diphenyl borate, in combination with cisplatin, cell survival was significantly increased, and the expression of ER stress related proteins GRP78, CHOP, and apoptotic protein caspase-3 was significantly decreased [57]. Studies have shown that OvCa may trigger the ER stress response, rapid activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axis, so that the dynamic imbalance between saturated and unsaturated fatty acids leads to ovarian cancer cell fate [58]. In recent years, the study of the role of exercise combined with herbal medicine therapy and dietary modification on OvCa has also become a hotspot. Increasing berberine concentration [59] was found to gradually enhance the expression of autophagy-associated protein and microtubule-associated protein 1 light chain 3 (LC3) and ubiquitin-binding protein p62 in SKOV3 cells, and significantly increase the expression of ER stress associated proteins, GRP78 and CHOP, and autophagy-associated proteins, beclin-1 and LC3. Exercise combined with berberine inhibited ER stress occurrence and autophagy in SKOV3 cells. In an investigation of the molecular mechanism of the induction of apoptosis in SKOV3 cells with the combination of the Chinese herbal medicine Chonglou saponin VII and cisplatin, increased expression of caspase 3 and apoptosis induction were observed. Meanwhile, the increased expression of XBP1 and ATF4 indirectly demonstrated that Chonglou saponin induced apoptosis in SKOV3 cells by activating the caspase pathway through ER stress [60]. At present, there are relatively few studies on the prevention and treatment of ovarian cancer through exercise regulating ER stress pathways. Exercise intervention can effectively alleviate fatigue and improve the quality of life of patients with OvCa, and long-term exercise training can regulate mitsugumin 53, a muscle-specific TRIM family protein, expression, which may reduce the risk of OvCa development [61]. Studying the regulatory effect and mechanism of exercise combined with herbal medicine, cognitive-behavioral therapy, and traditional Chinese medicine on OvCa is a potentially promising approach to OvCa treatment [62]. 2.3 Cervical cancer Cervical cancer is a malignant neoplasm occurring on the squamous and glandular epithelium of the uterine cervix. Studies have shown that high-risk human papillomavirus (HPV) infection is a major contributor to cervical lesions and cervical cancer [63]. HPV-16 and HPV-18, two high-risk HPV viral infections, are the most common types of infection in patients with cervical carcinoma [64]. Generally, the high incidence of in situ cancer is in the age range of 30-35 years and that of invasive cancer is 45-55 years, although, in recent years, its incidence is also showing a younger age trend. Fortunately, the widespread use of cervical cytology screening in recent decades has enabled early detection and treatment of cervical carcinoma and precancerous lesions, and the incidence and mortality rates of cervical cancer have generally decreased. Currently, cervical cancer treatment includes surgery, chemotherapy, and radiotherapy, although many patients eventually die from metastasis and recurrence of cervical carcinoma. Studies have shown that [65] ER stress is closely associated with the occurrence and development of a variety of tumor diseases. The expression levels of ER stress related proteins can reflect different degrees of ER stress, and the processes of cellular reproduction and apoptosis are disrupted after ER stress occurrence. Since recent studies have found that HPV infection is closely associated with ER stress, studying the relationship between the expression levels of ER-related proteins and HPV infection has significant clinical implications. It was found that treatment of HeLa cells with curcumin led to increased expression of GRP78 and CHOP at the transcriptional and translational levels accompanied by inhibition of proliferation and occurrence of apoptosis. Quercetin induced apoptosis and ER stress by upregulating mRNA expression levels of eIF2α, ATF4, IRE1, XBP1, ATF6, PERK and CHOP in the HeLa cells. The up-regulating of mRNA expression level of GRP78 and activation of UPR are a molecular basis of quercetin-induced ER stress [66, 67]. Accordingly, they recently used RNA interference to silence Derlin-1 expression in overexpressed HPV16 E6 cells and found that decreased Derlin-1 expression was associated with no significant change in beclin-1 expression whereas p62 expression was increased. It is suggested that in the ER stress environment of HPV16 infection, Derlin-1 knockdown can affect the degradation of the p62 protein, leading to the blockage of the autophagic pathway. Derlin-1 is involved in the autophagic process during the autophagic-lysosome degradation phase and may serve as a communicating molecule between the ubiquitin-proteasome and autophagic-lysosomal pathways. These two protein degradation pathways may play a synergistic role in the ER stress process for maintaining cellular homeostasis, and this mechanism may be involved in HPV16-caused cervical cancer [68]. The expression rates of GRP78, c-Jun amino-terminal kinase, and enhancer-binding protein homologous protein were significantly higher in patients with high-risk HPV-16, HPV-18 infection, and cervical cancer than in low-risk HPV-6 infected and HPV-negative patients; additionally, the occurrence of HPV infection in cervical cancer cell lines was associated with the expression levels of ER stress related proteins [69]. The study showed that the FNDC3B was significantly upregulated in cervical cancer tissues. The immunofluorescence results obtained from the human protein atlas indicated that the FNDC3B protein is located in the ER and that it may play an oncogenic role in cancer development through ER stress, UPR, cell migration, and invasion [70]. The above study illustrates that the expression level of ER stress related proteins is associated with the occurrence and development of cervical cancer. ER stress activation might have a high value in the treatment and prognosis of cervical cancer and has good clinical prospects [71, 72]. The study has shown that the high expression of motor factor (AMF) in cervical cancer tissues is related to malignant biological characteristics and poor prognosis [73]. It is known that exercise can secrete motor factors. Our previous studies have shown that the motor factor irisin can inhibit apoptosis by regulating the IRE1α /XBP1 and IRE1α-TXNIP/ROS-NLRP3 pathways of ER stress [74, 75]. It is speculated that exercise secretion of motor factors may also play a beneficial role in the pathological process of cervical cancer by inhibiting ER stress pathways. The benefits of exercise in preventing cervical cancer in patients include improved physical function, fatigue, sleep quality, quality of life, anxiety, and depression, and may even reduce the risk of recurrence and prolong survival. However, to date, few studies have examined whether exercise exerts anticancer effects through modulation of the ER stress pathway, and further research is needed to determine the exact molecular mechanisms linking exercise to ER stress in the development of cervical carcinomas and to assess the potential of its associated pathways as novel therapeutic targets for the treatment of these diseases. 2.4 Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is a common clinical disease of heterogeneous, multifactorial, genetic, and endocrine complex disorders in women of reproductive age, with a prevalence of 8–10% [76]. The main manifestations are amenorrhea or scanty menstruation, hyperandrogenism, polycystic ovarian, ovulatory dysfunction, etc., often accompanied by metabolic syndromes such as infertility, obesity, insulin resistance, and dyslipidemia. It is also a key factor in the development of pregnancy complications, diabetes, cardiovascular disease, and endometrial cancer [77, 78]. Despite the increasing incidence of PCOS, its etiology is not specifically documented. Research has found that the relative expression of BIP mRNA and protein was significantly higher in the PCOS observation group than in the control group; similarly, the relative expression of CHOP mRNA and protein tended to be higher in the PCOS observation group than in the control group, although there was no significant difference [79]. The result several genes involved in UPR er and UPR mt were overexpressed in the GCs of PCOS-IR. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR [80]. The expression of the ER stress markers GRP78, CHOP and XBP1s in the cumulus cells was higher in PCOS patients than in control patients, as were the levels of the UPR sensor proteins p-IRE1α, p-EIF2α and GRP78 [81]. ER stress triggers insulin resistance, and IR is the pathological basis of PCOS [82, 83]. Studies have shown that the reduction of granulosa cells in PCOS ovaries may be related to their apoptosis [84], although the exact molecular mechanism of granulosa cell-induced follicular atresia is not yet clear. Although research is still focused on the death ligand/receptor-dependent and mitochondria-dependent apoptotic pathways, the ER stress mediated apoptotic pathway in granulosa cells has also attracted increasing attention in recent years. Sigma-1 receptor is involved in diminished ovarian reserve possibly by influencing endoplasmic reticulum stress-mediated granulosa cells apoptosis [85]. ER stress mediated granulocyte apoptosis might contribute to the pathogenesis of PCOS. PCOS ovarian granulosa cells have multi-signaling molecule anomalies, such as the abnormal expression of insulin receptors α and β and their receptor substrate-1, decreased activity of insulin receptor, insulin receptor substrate 1 [86], and phosphatidylinositol 3-kinase in patients with PCOS, and decreased expression of glucose transporter protein 4, resulting in the occurrence of IR and decreased glucose uptake. ER stress is hypothesized to affect the apoptosis of granulosa cells by causing IR. Granulosa cells are protected by the upregulated expression of BIP within them. However, the CHOP-dependent apoptotic pathway is not yet activated, thus allowing the granulosa cells to persist, resulting in many antral follicles in patients with PCOS. Previous studies have shown that aerobic exercise and curcumin improve follicular dysfunction in PCOS by inhibiting the IRE1α-XBP1 pathway of ER stress, and exercise-induced modulation of secreted myokine irisin improves follicular insufficiency in PCOS by inhibiting granulosa cell apoptosis through the IRE1α/thioredoxin interacting protein (TXNIP) axis of ER stress [74, 75]. However, exercise recommendations are vague and, therefore, difficult to implement owing to the lack of data on the type, intensity, or duration of exercise that produces benefits for women with PCOS. Well-designed trials are needed to guide the clinical management of PCOS in women of reproductive age. The focus should be on the role of exercise therapy in the prevention of PCOS to help develop individualized, appropriate types and intensities of exercise, and targeted exercise prescriptions to prevent the disease. 2.5 Endometriosis Endometriosis (EMT) is a benign estrogen-dependent disease associated with pelvic pain and infertility, characterized by the ectopic distribution of endometrial tissue, mainly in the pelvic peritoneum and ovaries [87]. Currently, in patients with EMs, progestin resistance is an emerging feature of the disease, in addition to estrogen dependence. EMT is a chronic disease defined as a "benign cancer" requiring lifelong management, and despite its high prevalence, treatment outcomes have been unsatisfactory owing to the complexity of its pathogenesis and the diversity of its symptoms, making it a hot topic in gynecologic research [88]. Recent studies have shown that the occurrence of EMT is associated with abnormal apoptosis [89, 90], and ER stress mediated apoptosis is one of the important pathways. The expression of phosphoinositide-kinase/protein kinase B (P13K/AKT) and GRP78 was shown to be significantly higher in ectopic endometrial lesion tissues than in normal endometrial tissues [91, 92]. High P13K/AKT pathway expression is one of the important mechanisms of ectopic endometrial mesenchymal cell migration. ER stress acts in cooperation with the P13K/AKT signaling pathway and is jointly involved in EMT pathogenesis [93]. Research has found that excessive reactive oxygen species induces senescence of endometriosis granular cells via arouse ER stress, which finally contributes to endometriosis-associated infertility, and melatonin may represent a novel adjuvant therapy strategy for endometriosis-associated infertility [94]. In addition, the mRNA and protein expression levels of GRP78, GRP94, caspase-12, and caspase-3 were also significantly lower in the proliferative and secretory ectopic endometrium of patients with EMT than in eutopic endometrium, this indicated that the ER stress mediated apoptotic pathway was more significantly downregulated in ectopic endometrium. Therapeutic induction of ER stress in endometriotic cells could promote apoptosis and contribute to the management of disease [95-97]. Therefore, novel therapeutic agents that focus on targeting ER stress induction may be an effective way to treat EMT. Exercise plays a significant role in the treatment and prevention of EMT [98-100], and studies have shown that exercise is beneficial in reducing the intensity of pelvic pain, controlling stress levels, and improving psychological well-being in patients with EMT, thus improving the quality of life. Regular, low-intensity aerobic exercise is beneficial in reducing the intensity of the pain in endometriosis and the size of the uterus. Exercise is beneficial in reducing the risk of developing infertility in EMT by increasing the levels of associated endocrine factors and alpha-amylase. Exercise is also beneficial in reducing the risk of EMT by shrinking EMT lesions through fatty acid synthase, matrix metalloproteinase-9, changes in proliferating cell nuclear antigen protein expression, and lowering serum testosterone levels. ER stress mediated downregulation of apoptotic pathways may be one of the important mechanisms of EMT pathogenesis, which provides important clues for the in-depth study of the exact mechanism of EMT pathogenesis. Exercise modulates ER stress induced autophagy and apoptosis. In addition, exercise can inhibit inflammatory responses, oxidative stress, angiogenesis, and dysregulation of apoptosis. These are the underlying pathophysiological triggers that lead to EMT. Therefore, finding the proper prescription exercise, developing individualized exercise programs, and exploring targeted anti-over-ER stress, anti-inflammatory, antioxidant, anti-angiogenic, and apoptotic modulators are strategies and approaches to treat EMT disease. Conclusion and outlook In summary, the ER stress process is complex and plays an important role in common female diseases. The study of ER stress and UPR has led to the elucidation of the role of the ER as a "third interface" for cell signaling alongside the cell membrane and nucleus. ER stress is very closely associated with several aging-related diseases, including neurodegenerative, inflammatory, and metabolic diseases and tumors. Exercise, as a convenient and non-invasive means of health promotion, effectively modulates and ameliorates ER stress related pathologies through the corresponding molecular mechanisms. Currently, there are no clear conclusions about the effects of different exercise modalities, intensity, and duration on ER stress intensity and stress duration in different tissues. Therefore, exploring the effects of different exercise modalities on different levels of ER stress disease remains a hot topic of research in the field of health and biomedicine. Exploring the role of the exercise-ER stress-autophagy pathway in regulating the survival of common gynecologic tumor cells provides a new theoretical basis for tumor treatment. However, many aspects of ER stress are still unknown. With the progressive study of the regulatory mechanisms of ER stress and UPR signaling pathways and molecules, IRE1-XBP1, PERK, and ATF-6, further understanding of the mechanisms of development of common gynecological diseases at the cellular and molecular levels, by activating or inhibiting these pathways, may be beneficial for the treatment of relevant diseases. The scientific exercise program may provide new strategies for immunotherapy in women's health. Declarations Funding This research was supported by the Research Foundation for Youth Scholars of Jiaxing University (00323023AL and CD70522025). Author Contributions DC,SS, LC and JZ wrote the draft. YZ, SZ and YW revised the text. All authors contributed to the article and approved the submitted version. Conflict of Interest The authors declare that this editorial was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Jonas Bloch Thorlund, Milena Simic, Kenneth Pihl, et al. Similar Effects of Exercise Therapy, Nonsteroidal Anti-inflammatory Drugs, and Opioids for Knee Osteoarthritis Pain: A Systematic Review with Network Meta-analysis[J]. J Orthop Sports Phys Ther , 2022, 52(4):207-216. Jonathan M Memme, Avigail T Erlich, Geetika Phukan, et al. Exercise and mitochondrial health[J]. J Physiol , 2021, 599(3):803-817. Shengqi He, Tingting Fu, Yue Yu, et al. IRE1α regulates skeletal muscle regeneration through Myostatin mRNA decay[J]. J Clin Invest , 2021, 131(17): e143737. Ing-Shiow Lay, Wei-Wen Kuo, Marthandam Asokan Shibu, et al. Exercise training restores IGFIR survival signaling in d-galactose induced-aging rats to suppress cardiac apoptosis[J]. J Adv Res , 2020, 28:35-41. Corey R.Hart, Zachary C.Ryan, Kyle T Pfaffenbach, et al. Attenuated activation of the unfolded protein response following exercise in skeletal muscle of older adults[J]. Aging (Albany NY) , 2019, 11(18): 7587-7604. Fengwu Li, Xiaokun Geng, Hangil Lee, et al. Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress[J]. Front Cell Neurosci . 2021, 15: 598230. Takashi Yamada, Yuki Ashida, Katsuyuki Tamai, et al. Improved skeletal muscle fatigue resistance in experimental autoimmune myositis mice following high-intensity interval training[J]. Arthritis Res Ther . 2022, 24(1): 156. Yuan Zhang, Yuting Liu , Xiaowei Liu, et al. Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice[J]. Oxid Med Cell Longev . 2022, 2022: 2297268. Guangqi Wang , Fengjuan Fan, Chunyan Sun, et al. Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?[J]. Cancers (Basel) , 2022, 14(21):5340. Ze Liu, Guanlin Liu, Dat P Ha, et al. ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator[J]. Proc Natl Acad Sci U S A . 2023, 120(31): e2303448120. Jun Ren, Yaguang Bi, James R Sowers, et al. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases[J]. Nat Rev Cardiol , 202, 18(7): 499-521. Megan C Kopp, Natacha Larburu, Vinoth Durairaj, et al. UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor[J]. Nat Struct Mol Biol . 2019, 26(11): 1053-1062. Hai Hu, Mingxing Tian, Chan Ding, et al. The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection[J]. Front Immunol , 2019, 9: 3083. Yiming Li, Yunshan Guo, Juan Tang, et al. New insights into the roles of CHOP-induced apoptosis in ER stress[J]. Acta Biochim Biophys Sin (Shanghai) . 2014, 46(8): 629-40. Xudan Liu, Yao Chen, Huanhuan Wang, et al. Microglia-derived IL-1β promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK/eIF2α/ATF4/CHOP upon arsenic exposure[J]. J Hazard Mater . 2021, 417: 125997. Stephan Mueller, Ephraim B Winzer, André Duvinage, et al. Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial[J]. JAMA , 2021, 325(6): 542-551. Yuxiao Liao, Zhao Peng, Liangkai Chen, et al. Prospective Views for Whey Protein and/or Resistance Training Against Age-related Sarcopenia[J] . Aging Dis , 2019,10(1)；157-173. Leslie A. Consitt, Courtney Dudley, Gunjan Saxena. Impact of Endurance and Resistance Training on Skeletal Muscle Glucose Metabolism in Older Adults[J]. Nutrients , 2019, 11(11): 2636. Antonella Muscella, Erika Stefàno, Santo Marsigliante. The effects of exercise training on lipid metabolism and coronary heart disease[J]. Am J Physiol Heart Circ Physiol , 2020, 319(1): H76-H88. Seyedeh Hoda Seyedizadeh, Sadegh Cheragh-Birjandi, Mohammad Reza Hamedi Nia. The Effects of Combined Exercise Training (Resistance-Aerobic) on Serum Kinesin and Physical Function in Type 2 Diabetes Patients with Diabetic Peripheral Neuropathy (Randomized Controlled Trials) [J]. J Diabetes Res , 2020, 2020: 6978128. Soo LS，Ho YJ，Seok SY. Effect of the low- versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus[J]. J Phys Ther Sci , 2015, 27(10): 3063-3068. Brisamar Estébanez, José A de Paz, María J Cuevas, et al. Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update[J]. Front Physiol , 2018, 9:1744. Emanuel Passos, Cidália Pereira, Inês O Gonçalves, et al. Physical exercise positively modulates nonalcoholic steatohepatitis-related hepatic endoplasmic reticulum stress[J]. J Cell Biochem , 2022, 123(10): 1647-1662. Bozi LH, Jannig PR, Rolim N, et al. Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats[J]. J Cell Mol Med , 2016, 20(11): 2208-2212. Bruno B Marafon, Ana P Pinto, Eduardo R Ropelle, et al. Muscle endoplasmic reticulum stress in exercise[J]. Acta Physiol (Oxf) , 2022, 235(1): e13799. Matheus Santos de Sousa Fernandes, Georgian Badicu, Gabriela Carvalho Jurema Santos, et al. Physical Exercise Decreases Endoplasmic Reticulum Stress in Central and Peripheral Tissues of Rodents: A Systematic Review[J]. Eur J Investig Health Psychol Educ , 2023, 13(6): 1082-1096. Li F, Liu BB, Cai M, et al. Excessive endoplasmic reticulum stress and decreased neuroplasticity-associated proteins in prefrontal cortex of obese rats and the regulatory effects of aerobic exercise[J]. Brain Res Bull , 2018, 140: 52-59. Ling Ruan, Fanghui Li, Shoubang Li, et al. Effect of Different Exercise Intensities on Hepatocyte Apoptosis in HFD-Induced NAFLD in Rats: The Possible Role of Endoplasmic Reticulum Stress through the Regulation of the IRE1/JNK and eIF2 α/CHOP Signal Pathways[J]. Oxid Med Cell Longev . 2021, 2021: 6378568. Pontus Boström, Jun Wu, Mark P Jedrychowski, et al. A PGC1-α-dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis[J]. Nature , 2012, 481(7382):463-468. Jyotirmaya Behera, Jessica Ison, Michael J Voor, et al. Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis[J]. Diabetes , 2022, 71(12): 2777-2792. Wu J, Ruas JL, Estall JL, et al. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC- 1α/ATF6α complex[J]. Cell Metab , 2011, 13(2):160-169. Khadir A, Kavalakatt S, Abubaker J, et al. Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone[J]. Metabolism ，2016, 659(9): 1409-1420. Kim K, Ahn N, Jung S, et al. Effects of intermittent ladder-climbing exercise training on mitochondrial biogenesis and endoplasmic reticulum stress of the cardiac muscle in obese middle-aged rats[J]. Korean J Physiol Pharmacol , 2017, 21(6): 633-641. Bohnert KR, Mcmillan JD, Kumar A. Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease[J]. J Cell Physiol , 2018, 233: 67-78. Bruno B Marafon, Ana P Pinto, Eduardo R Ropelle, et al. Muscle endoplasmic reticulum stress in exercise[J]. Acta Physiol (Oxf). 2022, 235(1): e13799. Rebecca H Johnson, Carey K Anders, Jennifer K Litton, et al. Breast Cancer in Adolescents and Young Adults[J]. Pediatr Blood Cancer , 2018, 65(12): e27397. C Sessa, J Balmaña, S L Bober, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline[J]. Ann Oncol , 2023, 34(1): 33-47. Alison Laws, Rinaa S Punglia. Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer[J]. J Clin Oncol , 2023, 41(17): 3092-3099. Anna Kawiak. Molecular Research and Treatment of Breast Cancer[J]. Int J Mol Sci , 2022, 23(17):9617. ZHU Pei，LIU Ya-kun，JIANG Yu, et al. Ethanol promotes the progression of breast cancer in mice by activating endoplasmic reticulum stress[J]. ACTA LABO Ｒ ATO Ｒ IUM ANIMALIS SCIENTIA SINICA , 2017, 25(6): 605-610. Tzu-Jung Yu, Jun-Ping Shiau, Jen-Yang Tang, et al. Physapruin A Exerts Endoplasmic Reticulum Stress to Trigger Breast Cancer Cell Apoptosis via Oxidative Stress[J]. Int J Mol Sci, 2023, 24(10): 8853. Yujin Jin, Diem Thi Ngoc Huynh, Kyung-Sun Heo. Ginsenoside Rh1 inhibits tumor growth in MDA-MB-231 breast cancer cells via mitochondrial ROS and ER stress-mediated signaling pathway. Arch Pharm Res . 2022, 45(3): 174-184. Jesús E Serrano-Negrón, Zhenbo Zhang, Andrea P Rivera-Ruiz, et al. Tunicamycin-induced ER stress in breast cancer cells neither expresses GRP78 on the surface nor secretes it into the media[J]. Glycobiology . 2018, 28(2): 61-68. Tao SS, Chen L. Role of a novel endoplasmic reticulum stress-inducible protein TRIM25 in breast cancer cells[J]. Journal of Integration Technology , 2020, 9(1): 45-54. Weixi Jiang, Li Chen, Xun Guo, et al. Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy[J]. Theranostics . 2022, 12(6): 2987-3006. Yifeng Zheng, Pengxi Liu, Neng Wang, et al. Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway[J]. Oxid Med Cell Longev . 2019, 2019: 8781690. Seo Yeon Lee, Tae Hoon Kim, Won Geun Choi, et al. SH003 Causes ER Stress-mediated Apoptosis of Breast Cancer Cells via Intracellular ROS Production[J]. Cancer Genomics Proteomics . 2023, 20(1): 88-116. Halima Alsamri, Aysha Alneyadi, Khalid Muhammad, et al. Carnosol Induces p38-Mediated ER Stress Response and Autophagy in Human Breast Cancer Cells[J]. Front Oncol . 2022, 12:911615. Wenyu Ma. Berberine and regular exercise synergetically inhibit the progression of breast cancer by mediating SCFAs and immune regulation[J]. Southwest University, 2021. 1: 1-81. Antonieta Alvarado, Rui M Gil da Costa, Ana I Faustino-Rocha. Effects of exercise training on breast cancer metastasis in a rat model[J]. Int J Exp Pathol . 2017, 98(1): 40-46. Huiying Ma, Tian Tian, Zhumei Cui. Targeting ovarian cancer stem cells: a new way out[J]. Stem Cell Res Ther , 2023, 14(1): 28. Ruiqian Zhang, Michelle K Y Siu, Hextan Y S Ngan, et al. Molecular Biomarkers for the Early Detection of Ovarian Cancer[J]. Int J Mol Sci . 2022, 23(19):12041. Hui-Di Zhang , Jian-Ni Huang, Yun-Zi Liu, et al. Endoplasmic Reticulum Stress and Proteasome Pathway Involvement in Human Podocyte Injury With a Truncated COL4A3 Mutation[J]. Chin Med J (Engl) . 2019, 132(15):1823-1832. Jiahang Mo, Shunyi Ruan, Baicai Yang, et al. A novel defined risk signature of endoplasmic reticulum stress-related genes for predicting the prognosis and immune infiltration status of ovarian cancer[J]. J Zhejiang Univ Sci B . 2023, 24(1): 64-77. Entaz Bahar, Ji-Ye Kim, Dong-Chul Kim, et al. Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway[J]. Int J Mol Sci , 2021, 22(8): 3916. Xueping Chen, Zhiqiang Zha, Yu Wang, et al. Knockdown of ENTPD5 inhibits tumor metastasis and growth via regulating the GRP78/p-eIF-2α/CHOP pathway in serous ovarian cancer[J]. J Ovarian Res , 2022, 15(1): 69. Xiao Zhenghong, Xie Guanglun, Zhai Huange, et al. Silent Galectin-3 induces apoptosis and endoplasmic reticulum stress in ovarian cancer cells in invitro[J]. Modern Oncology, 2020, 28 (10): 1638-1642. Guangyuan Zhao, Yuying Tan, Horacio Cardenas, et al. Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids[J]. Proc Natl Acad Sci U S A . 2022, 119(41): e2203480119. Shekufe Rezghi Barez, Ahmad Movahedian Attar, Mahmoud Aghaei. MicroRNA-30c-2-3p regulates ER stress and induces apoptosis in ovarian cancer cells underlying ER stress[J]. EXCLI J. 2021, 20: 922-934. ZHANG Jia-ling, ZHENG Chuan-jun, YAN Rui-qi, et al. Apoptosis of ovarian cancer cells induced by polyphyllin VII and cisplatin through endoplasmic reticulum stress[J]. Chin J Lab Diagn , 2015, 19(1): 6-9. Qiu Xijian, Huang Yiwu, Xu Meihu. Effect of Qizaoyixue decoction with exercise on cancer-related fatigue for oophoroma patients duringintermittent chemotherapy[J]. Modern Nursing ，2011, 14: 1646-1649. Suzanne C Dixon-Suen, Sarah J Lewis, Richard M Martin, et al. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study[J]. Br J Sports Med . 2022, 56(20): 1157-1170. Lisa Rahangdale, Chemtai Mungo, Siobhan O'Connor, et al. Human papillomavirus vaccination and cervical cancer risk[J]. BMJ , 2022, 379: e070115. Arvind Krishnamurthy, Vijayalakshmi Ramshankar. Current Status and Future Perspectives of Molecular Prevention Strategies for Cervical Cancers[J]. Indian J Surg Oncol , 2020, 11(4): 752-761. Haowen Dou, Shasha Yang, Yulai Hu, et al. Sesamin induces ER stress-mediated apoptosis and activates autophagy in cervical cancer cells[J]. Life Sci . 2018, 200: 87-93. Boyun Kim, Hee Seung Kim, Eun-Ji Jung, et al. Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells[J]. Mol Carcinog . 2016, 55(5): 918-928. Xiu-Mei Li, Jing Liu, Fang-Fang Pan, et al. Quercetin and aconitine synergistically induces the human cervical carcinoma HeLa cell apoptosis via endoplasmic reticulum (ER) stress pathway[J]. PLoS One . 2018, 13(1): e0191062. Ren Songjie, Lv Juan, Li Jiang, et al. Effect of endoplasmic reticulum-related degradation protein Derlin-1 on autophagy pathway of cervical cancer C33A cells[J]. J Shanxi Med Univ , 2020, 51(3): 198-202. Zhijia Li, Muzhou Teng, Yajie Wang, et al. The mechanism of 5-aminolevulinic acid photodynamic therapy in promoting endoplasmic reticulum stress in the treatment of HR-HPV-infected HeLa cells[J]. Photodermatol Photoimmunol Photomed . 2021, 37(4):348-359. Bing Han, Hongbo Wang, Jianzhao Zhang. FNDC3B Is Associated with ER Stress and Poor Prognosis in Cervical Cancer[J]. Oncol Lett . 2020, 19(1): 406-414. Xue Liu, Jing Song, Hui Liu, et al. Endoplasmic Reticulum Stress Could Predict the Prognosis of Cervical Cancer and Regulate the Occurrence of Radiation Mucositis[J]. Dose Response . 2023, 21(2):15593258231173199. Jagoda Adamczyk-Grochala, Dominika Bloniarz, Klaudia Zielinska, et al. DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis[J]. Apoptosis . 2023, 28(1-2):166-185. BING Qing. Expression and clinical significance of AMF in cervical cancer[J]. Journal of China Prescription Drug . 2021, 19(05). Yaling Zhang, Yajing Weng, Daojuan Wang, et al. Curcumin in combination with aerobic exercise improves follicular dysfunction via inhibition of the hyperandrogen-induced IRE1α/XBP1 endoplasmic reticulum stress pathway in PCOS-like rats[J]. Oxidative Medicine and Cellular Longevity . 2021, 2021:7382900. Yajing Weng, Yaling Zhang, Daojuan Wang, et al. Exercise-induced Irisin improves follicular dysfunction by inhibiting IRE1α-TXNIP/ROS-NLRP3 pathway in PCOS[J]. J Ovarian Res . 2023, 16(1): 151. Heather G Huddleston 1, Anuja Dokras . Diagnosis and Treatment of Polycystic Ovary Syndrome[J]. JAMA , 2022, 327(3): 274-275. Dumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome[J]. Endocrine Reviews . 2015, 36:487-525. Elisabet Stener-Victorin 1, Qiaolin Deng. Transmission of Polycystic Ovary Syndrome via Epigenetic Inheritance[J]. Trends Mol Med , 2021, 27(8):723-724. Hiroshi Koike, Miyuki Harada, Akari Kusamoto, et al. Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome[J]. Front Endocrinol (Lausanne) , 2023, 14: 1124405. Mauro Cozzolino, Sonia Herraiz, Yigit Cakiroglu, et al. Distress response in granulosa cells of women affected by PCOS with or without insulin resistance[J]. Endocrine . 2023, 79(1): 200-207. Jiamin Jin, Yerong Ma, Xiaomei Tong, et al. Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK[J]. Hum Reprod . 2020, 35(5): 1145-1158. Chantal Anifa Amisi. Markers of insulin resistance in Polycystic ovary syndrome women: An update[J]. World J Diabetes , 2022, 13(3):129-149. Yan Peng, Liyuan Guo, Anxin Gu, et al. Electroacupuncture alleviates polycystic ovary syndrome-like symptoms through improving insulin resistance, mitochondrial dysfunction, and endoplasmic reticulum stress via enhancing autophagy in rats[J]. Mol Med , 2020, 26(1):73. Jerilee M K Azhary, Miyuki Harada, Nozomi Takahashi. Endoplasmic Reticulum Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS[J]. Endocrinology . 2019, 160(1): 119-132. Lile Jiang, Jinquan Cui, Cuilian Zhang, et al. Sigma-1 receptor is involved in diminished ovarian reserve possibly by influencing endoplasmic reticulum stress-mediated granulosa cells apoptosis[J]. Aging (Albany NY) , 2020, 12(10): 9041-9065. Bojana Mićić, Ana Djordjevic, Nataša Veličković，et al. AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding[J]. Biomedicines , 2023, 11(6): 1586. Patricia Ribeiro de Carvalho França, Anna Carolina Pereira Lontra, Patricia Dias Fernandes. Endometriosis: A Disease with Few Direct Treatment Options[J]. Molecules . 2022, 27(13): 4034. Andrew W Horne, Stacey A Missmer. Pathophysiology, diagnosis, and management of endometriosis[J]. BMJ , 2022, 379: e070750. Sudipta Dutta, Sakhila K Banu, Joe A Arosh. Endocrine disruptors and endometriosis[J]. Reprod Toxicol , 2023, 115:56-73. Elif Bilgic , Elif Guzel , Sevil Kose, et al. Endocannabinoids Modulate Apoptosis in Endometriosis and Adenomyosis[J]. Acta Histochem , 2017, 119(5):523-532. Lama Assaf, Assaad A Eid, Joseph Nassif. Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis[J]. Life Sci . 2022, 306: 120805. JongYeob Choi, MinWha Jo, EunYoung Lee, et al. Nuclear factor-kappa B signaling in endometriotic stromal cells is not inhibited by progesterone owing to an aberrant endoplasmic reticulum stress response: a possible role for an altered inflammatory process in endometriosis[J]. Mol Hum Reprod , 2021, 27(2): gaab002. Park S, Lim W, Bazer FW, et al. Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells[J]. J Cell Physiol , 2018, 233(4): 3055-3065. Xiang Lin, Yongdong Dai, Xiaomei Tong, et al. Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility[J]. Redox Biol , 2020, 30:101431. Hussein Riyadh Abdul Kareem Al-Hetty, Ahmed Darweesh Jabbar, Vladimir F Eremin , et al. The role of endoplasmic reticulum stress in endometriosis[J]. Cell Stress Chaperones , 2023, 28(2): 145-150. Sara Hansen, Una Á Sverrisdóttir, Martin Rudnicki. Impact of exercise on pain perception in women with endometriosis: A systematic review[J]. Acta Obstet Gynecol Scand , 2021, 100(9): 1595-1601. Chisato Kunitomi, Miyuki Harada, Nozomi Takahashi, et al. Activation of endoplasmic reticulum stress mediates oxidative stress-induced apoptosis of granulosa cells in ovaries affected by endometrioma[J]. Mol Hum Reprod . 2020, 26(1): 40-52. Sara Hansen, Una Á Sverrisdóttir, Martin Rudnicki. Impact of exercise on pain perception in women with endometriosis: A systematic review[J]. Acta Obstet Gynecol Scand . 2021, 100(9): 1595-1601. Zahra Salehpoor, Bahia Namavar Jahromi, Nader Tanideh, et al. High intensity interval training is superior to moderate intensity continuous training in enhancing the anti-inflammatory and apoptotic effect of pentoxifylline in the rat model of endometriosis[J]. J Reprod Immunol . 202, 156: 103832. J C Rosa-E-Silva, M L Montenegro, J Meola, et al. Influence of Physical Exercise on Endometriosis Experimentally Induced in Rats[J]. J Minim Invasive Gynecol . 2015, 22(6S): S167. Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3704046","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":259079627,"identity":"1c522cee-fa7b-47fd-af05-92397bf0bda8","order_by":0,"name":"Dejian Chen","email":"","orcid":"","institution":"The First Hospital of Jiaxing or The Affiliated Hospital of Jiaxing University","correspondingAuthor":false,"prefix":"","firstName":"Dejian","middleName":"","lastName":"Chen","suffix":""},{"id":259079628,"identity":"9ba2971e-25d8-4d97-ba4b-ea3e0ff27c37","order_by":1,"name":"Shuo Zhang","email":"","orcid":"","institution":"Jiaxing 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00:18:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":667071,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3704046/v1/6d83a4b7-949f-40d7-bca1-07ed44310edc.pdf"},{"id":48239008,"identity":"6c8ca105-0179-43c5-9f77-f48e82657a69","added_by":"auto","created_at":"2023-12-15 00:02:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27905,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3704046/v1/0b8e1cbe6c53def44c86840a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eWith an improvement in the living standards and newfound health consciousness, an increasing number of people are devoting themselves to physical exercise, ranging from the \u0026quot;square dance\u0026quot; loved by middle-aged and older people to the \u0026quot;Wechat step ranking\u0026quot; used regularly by young individuals. Exercise has become a part of people\u0026apos;s lives. In China, August 8 has been celebrated as \u0026quot;National Fitness Day\u0026quot; since 2009. Exercise is essential for health and fitness, not only to improve immunity, cardiovascular function, and metabolism [1] but also from a cellular and molecular point of view since long-term exercise training can regulate ER stress and mitochondrial function and prevent apoptosis [2-4]. Currently, the incidence trend for cancer is increasing in younger adults. Breast, cervical, and ovarian cancers are still the most common causes of malignant tumor-related deaths in women. The World Health Organization currently advocates that countries strive for the following goals: \u0026gt; 90% coverage of human papillomavirus (HPV) vaccination of girls younger than 15 years; \u0026gt; 70% coverage of effective cervical carcinoma screening of adult women aged 35-45 years; and ensuring the acceptance of rational treatment and management by at least 90% of women with lesions, post-screening. As a non-invasive and economical health promotional tool, research to elucidate the role of exercise in common female diseases and related molecular mechanisms will provide a theoretical basis for the clinical treatment of women\u0026apos;s health. The effects of post-exercise-induced changes in the ER in several diseases have received increasing attention from researchers. The relationship between exercise and ER stress and the effect of exercise-regulated ER stress on the disease is a hot topic of research in the field of exercise and health and biomedicine. Numerous studies have shown that exercise can effectively ameliorate various ER stress-related disorders, including obesity, type 2 diabetes, cancer, neurodegeneration, osteoporosis, and sarcopenia, through different mechanisms [5-8]. The molecular mechanisms linking exercise regulation of ER stress to the development of some diseases still need to be actively explored.\u003c/p\u003e\n"},{"header":"Exercise and ER stress","content":"\u003cp\u003e1.1 Occurrence of ER stress\u003c/p\u003e\n\u003cp\u003eThe ER is an important organelle for the translation, synthesis, folding, and transport of protein and the storage of intracellular calcium ions in eukaryotic cells. The stability of the internal environment of the ER is essential for the realization of ER function, and therefore, homeostasis in the ER is highly maintained. Several stimuli, including ischemia-reperfusion injury, oxidative stress, metabolic intermediates such as homocysteine, excessive intracellular protein synthesis exceeding protein folding capacity, disorders of calcium metabolism in the ER, impaired lecithin synthesis, and several other physical, chemical, or genetic factors can trigger the ER stress, which, in turn, triggers the unfolded protein response (UPR). The UPR is mediated by an ER molecular chaperone, glucose-regulated protein 78/binding immunoglobulin protein (GRP78/BIP), and three ER stress transmembrane proteins [9, 10]. These three proteins are the double-stranded RNA (dsRNA)-dependent protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF-6), and inositol-requiring enzyme 1 (IRE-1). Under normal physiological conditions, the amino terminus of these three transmembrane proteins, PERK, ATF-6, and IRE-1, are bound to GRP78/BIP in an inactive state. When ER stress occurs, GRP78/BIP dissociates from these three proteins and binds to unfolded proteins. In contrast, dissociated stress proteins are activated and reduce the accumulation of misfolded or unfolded proteins in the ER by initiating the respective UPR pathway.\u003c/p\u003e\n\u003cp\u003eUPR is an adaptive response of cells that prevents cell death by removing misfolded proteins. However, in cases of unresolved stress, strong and persistent stimuli, and irreparable perturbances in the internal environment, the corresponding mechanisms are activated to induce apoptosis [11, 12]. Current research focuses on three main pathways. The first is the nuclear transcription factor CHOP (C/EBP homologous protein) pathway, which is the main pathway for ER stress to regulate apoptosis. When cells receive stimulation signals, CHOP, which is originally very low in content, starts to accumulate in large amounts and move from the cytoplasm to the nucleus. The downstream regulatory pathways of CHOP for apoptosis induction are through the following: i) mitochondria-dependent pathways, ii) death receptor pathway, and iii) other pathways, such as CHOP-ERO1\u0026alpha;, CHOP-CaMKII, PERK/eIF2\u0026alpha;/CHOP, CHOP-P21, Bag5-CHOP, and CHOP-FOXO3A pathways [13-15]. The second pathway is the JNK (c-Jun N-terminal kinase) pathway, which results from the sustained activation of IRE1 due to increased insulin synthesis, which, in turn, activates JNK by recruiting tumor necrosis factor receptor (TNFR) and apoptosis signal-regulating kinase 1 (ASK-1) to form the IRE1-TNFR-ASK1 complex, which activates JNK in cascade and induces \u0026beta;-cell apoptosis. The third pathway is the caspase-12-activated apoptotic pathway. The vital organs of the body are defended and protected through these above apoptotic \u0026nbsp;pathways. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1Exercise regulates ER stress\u003c/p\u003e\n\u003cp\u003eStudies have shown that different exercise programs can prevent and treat different conditions. Endurance training improves cardiovascular function [16], strength training reduces muscular dystrophy [17], and the combination of both training methods is beneficial for patients with type 2 diabetes [18]. Aerobic exercise is another positive approach to reducing plasma lipid abnormalities and improving the prognosis of cardiovascular disease [19]. However, there are no clear conclusions on the effects of different exercise modalities, exercise intensity, and exercise duration on the ER stress intensity, stress duration, and effects in different organs and tissues.\u003c/p\u003e\n\u003cp\u003eStudies have shown that long-term exercise can slow down ER stress and reduce insulin resistance. The IRE1-JNK pathway is the classical signaling pathway of ER stress that triggers insulin resistance, and numerous studies have now shown that long-term endurance exercise can alleviate the symptoms of type 2 diabetes, reduce blood glucose levels in the body, and improve the sensitivity of insulin receptor [20]. Exercise training in adolescents with type 2 diabetes significantly improved the expression levels of the blood ER stress related protein GRP78 by both low-intensity and high-intensity intermittent exercise [21]. It was found that rats trained at high intensity for 5 weeks experienced ER stress and significantly reduced expression of apoptosis-signaling proteins CHOP and ATF4 in the skeletal muscle compared to rats in the low-intensity and no-exercise groups [22]. In a 6-week endurance treadmill training exercise in the GK rats, which did not affect hepatic ER stress and the hepatic insulin signaling pathway in rats [23]. However, it improved the blood glucose levels in the GK rats and was beneficial in maintaining the steady-state amount of blood glucose levels, indicating that perhaps 6 weeks of endurance treadmill training was insufficient to reduce the expression of BIP and IRE1. Aerobic exercise is known to reduce the signature UPR protein induced by myocardial infarction and improve cardiac function in rats. However, short-term aerobic exercise is also insufficient to induce increased expression of myocardial protein GRP78 and CHOP [24, 25]. It was also reported that endurance exercise training also only mildly increased the expression of GRP78 in skeletal muscle [26]. The presence of ER stress in the prefrontal lobe of SD rats fed a high-fat diet to induce obesity and speculated that excess ER stress may play a key role in reducing the levels of neuroplasticity-related proteins [27]. However, aerobic exercise significantly reversed the expression of GRP78, p-PERK, p- eukaryotic initiation factor-2\u0026alpha; (eIF2\u0026alpha;), caspase-12, CHOP, and Bax/Bcl-2 in the prefrontal cortex of SD rats with obesity. After 3 weeks of high-intensity treadmill training of obese mice on a high-fat diet, the hypothalamus showed maximal ER stress but no apoptosis [22]. Collectively, the intensity of exercise, rather than its volume or duration, may play a critical role in magnifying the protective effect of exercise against nonalcoholic fatty liver disease [28]. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\u0026alpha;) is a co-transcription factor that is abundantly expressed in tissues that are active in energy metabolism, such as the cardiac muscle, skeletal muscle, brown fat, and brain. Exercise has been shown to increase PGC-1\u0026alpha; levels in the skeletal muscle, initiating the downstream factor fibronectin type III domain-containing protein (FNDC) 5 to promote fat thermogenesis by acting on peroxisome proliferator-activated receptor alpha (PPAR\u0026alpha;). Meanwhile, PPAR\u0026alpha; also increases the expression of uncoupling protein 1, activates brown fat-associated groups, and accelerates the browning of white fat to achieve weight loss [29, 30]. In PGC-1\u0026alpha; knockout mice experiments. It was found that by knocking out CHOP and thus blocking apoptosis in the ER stress related pathway, ATF6 \u0026alpha;-knockout mice could not recover from acute exercise on their own but could improve exercise intolerance [31]. 3-month aerobic exercise training resulted in decreased expression levels of ER stress related proteins, such as GRP78, p-IRE1, and p-eIF2\u0026alpha;, in the subcutaneous adipose tissue and peripheral blood mononuclear cells of obese individuals [32]. Reduced expression levels of both ER stress related proteins p-PERK and CHOP were also found in experiments combining intermittent stair-climbing training and reduced caloric intake [33]. Moderate exercise initially causes activation of the ER stress and UPR pathways, probably due to adaptation mechanisms in the skeletal muscle. However, after multiple training sessions, the ER stress and UPR-related signaling molecules, including BIP, GRP94, GADD34, and ATF4, are reduced [34]. Currently, more studies focus on the ER stress response of strength training-induced skeletal muscle [35]. However, in terms of the studies on adipose tissue, although diverse, the exercise forms are mainly aerobic; few studies have studied resistance training in the context of ER stress state and the inflammatory response in adipose tissue. Overall, moderate intensity and duration of exercise are holistic in their stimulatory effect and have protective and favorable effects on neurological, cardiovascular, and motor system diseases.\u003c/p\u003e"},{"header":"The beneficial role of exercise in the following diseases by regulating ER stress pathways ","content":"\u003cp\u003e2.1 Breast cancer\u003c/p\u003e\n\u003cp\u003eBreast cancer\u0026nbsp;(BC) has become a common malignancy threatening women\u0026apos;s health physically and mentally, and is prone to postoperative recurrence, with a high rate of malignant metastasis and an increasing incidence in younger adults [36]. Substantial evidence has revealed the effect of lifestyle and environmental factors on the development of BC, such as a high-fat diet, alcohol consumption, and lack of physical activity. The elimination of BC (primary prevention) may reduce morbidity and mortality. Secondary prevention, including diagnostic tests (e.g., mammography, ultrasonography, magnetic resonance imaging, molybdenum target mammography, breast self-examination, etc.), helps in the early detection of tumor-prone lesions [37, 38]. Although the postoperative 5-year survival rate of early BC can reach 80% [39], the postoperative distant recurrence and lung metastases adversely affect the overall survival rate for BC. Therefore, there is a need to further explore the signature oncogenes in BC cell growth and metastasis and to reveal their regulatory mechanisms in BC development.\u003c/p\u003e\n\u003cp\u003eOne study found accelerated tumor growth and metastasis in mice after they were made to consume alcohol; \u003cem\u003ein vitro,\u003c/em\u003e alcohol treatment significantly promoted BC cell proliferation and migration [40]. Alcohol chronic treatment induced a rise in the expression of reactive oxygen species (ROS) and ER stress activation protein p-eIF2a, BIP, and X-box binding protein 1 (XBP1)-s, and the reversal effect of 4-phenylbutyric acid (4-PBA) was observed on ethanol-induced chronic stress by pretreating E0771 cells, a murine BC cell line, with 4-PBA before ethanol treatment. Alcohol consumption is suggested to promote the malignant progression of BC cells through the induction of ER stress. ER stress inducer, tunicamycin, is a nucleotide antibiotic produced by actinomycetes. The mRNA and protein levels of ER stress-responsive genes (IRE1\u0026alpha; and BIP) were upregulated in breast cancer cells [41]. The results showed that ER stress induced apoptosis in MDA-MB-231 by upregulating the expression of\u0026nbsp;PERK, eIF2\u0026alpha;, ATF4,\u0026nbsp;CHOP, and caspase 4 that calpain could be a potential target for BC therapy [42]. A recent study [43] found that GRP78 was located intracellularly and not on the cell surface of the human BC cells MDA-MB-231 or it is secreted in the conditioned media. However, there is still a need to explore the signature oncogenes in BC cell growth and metastasis and to reveal their regulatory mechanisms in BC occurrence and development. Tripartite motif family protein (TRIM) 25 as a novel ER stress inducible protein that regulates the survival of BC cells by participating in ER stress induced apoptosis [44]. Recent research reports that combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy [45]. There is a study revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during BC tumor metastasis [46]. P38-mediated induction of ER stress response is autophagy in human breast cancer cells. Activation of endoplasmic reticulum stress mediated pathway is an important cause of apoptosis of breast cancer cells. [47, 48].\u003c/p\u003e\n\u003cp\u003ePresently, studies on the effect of exercise on ER stress in BC are scarce. In a study of exercise combined with berberine administration, changes in the expression of downstream apoptosis-related proteins induced by the mitochondrial pathway, Fas-mediated death receptor pathway, and ER stress pathway were suggested to be the mechanism by which exercise co-operates with berberine to delay breast tumor growth [49]. Exercise as an adjunct is thought to protect against cancer development and metastasis by reducing hormonal stimulation in hormone-dependent cancers or by decreasing the permeability of the blood vessel wall to the invading metastatic cells. Exercise training increased circulating estrogen levels in the rat model of ovarian cancer, but the exact mechanism is not fully understood. The ER plays an important role in processes such as protein folding for hormone synthesis. Therefore, additional studies are necessary to address the potential protective vascular changes involved in exercise training-modulated anti-metastatic effects of ER stress in BC [50]. As ER stress induced apoptosis in tumor cells is gradually gaining momentum in research, revealing novel regulatory mechanisms between the ER stress related proteins and pathways and BC can provide new ideas and theoretical support for the early diagnosis and clinical treatment of BC in the future.\u003c/p\u003e\n\u003cp\u003e2.2 Ovarian cancer\u003c/p\u003e\n\u003cp\u003eOvarian cancer\u0026nbsp;(OvCa) is also one of the common gynecologic malignancies and can occur at any age. Owing to the lack of reliable screening tests and the ambiguous symptoms, ovarian malignancies are not easily detected in early-stage lesions and lack effective treatment in advanced cases; consequently, their morbidity and mortality rates rank the topmost in gynecologic malignancies [51]. Currently, OvCa clinical treatment is mainly based on chemotherapy, although chemotherapeutic drugs have disadvantages such as causing severe adverse reactions, unclear targeting, and prone to developing drug resistance [52]. Therefore, finding efficient and targeted treatments for OvCa is an urgent problem, and studying the molecular pathogenesis of OvCa is of utmost importance for the treatment of OvCa.\u003c/p\u003e\n\u003cp\u003eStudies have shown that ER stress may play an important role in the anticancer activity of proteasome inhibitors.\u0026nbsp;ER stress-related genes are vital factors predicting the prognosis of OvCa, and possess great application potential in the clinic [53, 54]. Some scholars observed the effect of proteasome inhibitor MG132 on OvCa cell line SKOV3 \u003cem\u003ein vitro\u003c/em\u003e, and found that MG132 induced ER stress in SKOV3 cells, and the CHOP gene-mediated ER stress apoptotic pathway played an important role in the anti-OvCa activity of MG132 [55]. There was a\u0026nbsp;study demonstrated that ENTPD5 knockdown inhibited SOC cell proliferation, migration and restrained the activation of the GRP78/p-eIF-2\u0026alpha;/CHOP pathway, which provides a potentially effective therapeutic target for the treatment of OvCa [56]. In contrast, when SKOV3 cells were treated with the inositol 1,4,5-triphosphate inhibitor, 2-aminoethyl diphenyl borate, in combination with cisplatin, cell survival was significantly increased, and the expression of ER stress related proteins GRP78, CHOP, and apoptotic protein caspase-3 was significantly decreased [57]. Studies have shown that OvCa may trigger the ER stress response, rapid activation of IRE1\u0026alpha;/XBP1 and PERK/eIF2\u0026alpha;/ATF4 axis, so that the dynamic imbalance between saturated and unsaturated fatty acids leads to ovarian cancer cell fate [58].\u003c/p\u003e\n\u003cp\u003eIn recent years, the study of the role of exercise combined with herbal medicine therapy and dietary modification on OvCa has also become a hotspot. Increasing berberine concentration [59] was found to gradually enhance the expression of autophagy-associated protein and microtubule-associated protein 1 light chain 3 (LC3) and ubiquitin-binding protein p62 in SKOV3 cells, and significantly increase the expression of ER stress associated proteins, GRP78 and CHOP, and autophagy-associated proteins, beclin-1 and LC3. Exercise combined with berberine inhibited ER stress occurrence and autophagy in SKOV3 cells. In an investigation of the molecular mechanism of the induction of apoptosis in SKOV3 cells with the combination of the Chinese herbal medicine Chonglou saponin VII and cisplatin, increased expression of caspase 3 and apoptosis induction were observed. Meanwhile, the increased expression of XBP1 and ATF4 indirectly demonstrated that Chonglou saponin induced apoptosis in SKOV3 cells by activating the caspase pathway through ER stress [60].\u0026nbsp;At present, there are relatively few studies on the prevention and treatment of ovarian cancer through exercise regulating ER stress pathways. Exercise intervention can effectively alleviate fatigue and improve the quality of life of patients with OvCa, and long-term exercise training can regulate mitsugumin 53, a muscle-specific TRIM family protein, expression, which may reduce the risk of OvCa development [61]. Studying the regulatory effect and mechanism of exercise combined with herbal medicine, cognitive-behavioral therapy, and traditional Chinese medicine on OvCa is a potentially promising approach to OvCa treatment [62].\u003c/p\u003e\n\u003cp\u003e2.3 Cervical\u0026nbsp;cancer\u003c/p\u003e\n\u003cp\u003eCervical cancer is a malignant neoplasm occurring on the squamous and glandular epithelium of the uterine cervix. Studies have shown that high-risk human papillomavirus (HPV) infection is a major contributor to cervical lesions and cervical cancer [63]. HPV-16 and HPV-18, two high-risk HPV viral infections, are the most common types of infection in patients with cervical carcinoma [64]. Generally, the high incidence of in situ cancer is in the age range of 30-35 years and that of invasive cancer is 45-55 years, although, in recent years, its incidence is also showing a younger age trend. Fortunately, the widespread use of cervical cytology screening in recent decades has enabled early detection and treatment of cervical carcinoma and precancerous lesions, and the incidence and mortality rates of cervical cancer have generally decreased. Currently, cervical cancer treatment includes surgery, chemotherapy, and radiotherapy, although many patients eventually die from metastasis and recurrence of cervical carcinoma.\u003c/p\u003e\n\u003cp\u003eStudies have shown that [65] ER stress is closely associated with the occurrence and development of a variety of tumor diseases. The expression levels of ER stress related proteins can reflect different degrees of ER stress, and the processes of cellular reproduction and apoptosis are disrupted after ER stress occurrence. Since recent studies have found that HPV infection is closely associated with ER stress, studying the relationship between the expression levels of ER-related proteins and HPV infection has significant clinical implications. It was found that treatment of HeLa cells with curcumin led to increased expression of GRP78 and CHOP at the transcriptional and translational levels accompanied by inhibition of proliferation and occurrence of apoptosis. Quercetin induced apoptosis and ER stress by upregulating mRNA expression levels of eIF2\u0026alpha;, ATF4, IRE1, XBP1, ATF6, PERK and CHOP in the HeLa cells. The up-regulating of mRNA expression level of GRP78 and activation of UPR are a molecular basis of quercetin-induced ER stress [66, 67]. Accordingly, they recently used RNA interference to silence Derlin-1 expression in overexpressed HPV16 E6 cells and found that decreased Derlin-1 expression was associated with no significant change in beclin-1 expression whereas p62 expression was increased. It is suggested that in the ER stress environment of HPV16 infection, Derlin-1 knockdown can affect the degradation of the p62 protein, leading to the blockage of the autophagic pathway. Derlin-1 is involved in the autophagic process during the autophagic-lysosome degradation phase and may serve as a communicating molecule between the ubiquitin-proteasome and autophagic-lysosomal pathways. These two protein degradation pathways may play a synergistic role in the ER stress process for maintaining cellular homeostasis, and this mechanism may be involved in HPV16-caused cervical cancer [68]. The expression rates of GRP78, c-Jun amino-terminal kinase, and enhancer-binding protein homologous protein were significantly higher in patients with high-risk HPV-16, HPV-18 infection, and cervical cancer than in low-risk HPV-6 infected and HPV-negative patients; additionally, the occurrence of HPV infection in cervical cancer cell lines was associated with the expression levels of ER stress related proteins [69]. The study showed that the FNDC3B was significantly upregulated in cervical cancer tissues. The immunofluorescence results obtained from the human protein atlas indicated that the FNDC3B protein is located in the ER and that it may play an oncogenic role in cancer development through ER stress, UPR, cell migration, and invasion [70]. The above study illustrates that the expression level of ER stress related proteins is associated with the occurrence and development of cervical cancer.\u0026nbsp;ER stress activation might have a high value in the treatment and prognosis of cervical cancer and has good clinical prospects [71, 72].\u003c/p\u003e\n\u003cp\u003eThe study has shown that the high expression of motor factor (AMF) in cervical cancer tissues is related to malignant biological characteristics and poor prognosis\u0026nbsp;[73]. It is known that exercise can secrete motor factors. Our previous studies have shown that the motor factor irisin can inhibit apoptosis by regulating the IRE1\u0026alpha; /XBP1 and IRE1\u0026alpha;-TXNIP/ROS-NLRP3 pathways of ER stress\u0026nbsp;[74, 75]. It is speculated that exercise secretion of motor factors may also play a beneficial role in the pathological process of cervical cancer by inhibiting ER\u0026nbsp;stress\u0026nbsp;pathways.\u0026nbsp;The benefits of exercise in preventing cervical cancer in patients include improved physical function, fatigue, sleep quality, quality of life, anxiety, and depression, and may even reduce the risk of recurrence and prolong survival. However, to date, few studies have examined whether exercise exerts anticancer effects through modulation of the ER stress pathway, and further research is needed to determine the exact molecular mechanisms linking exercise to ER stress in the development of cervical carcinomas and to assess the potential of its associated pathways as novel therapeutic targets for the treatment of these diseases.\u003c/p\u003e\n\u003cp\u003e2.4 Polycystic ovary syndrome\u003c/p\u003e\n\u003cp\u003ePolycystic ovary syndrome (PCOS) is a common clinical disease of heterogeneous, multifactorial, genetic, and endocrine complex disorders in women of reproductive age, with a prevalence of 8\u0026ndash;10% [76]. The main manifestations are amenorrhea or scanty menstruation, hyperandrogenism, polycystic ovarian, ovulatory dysfunction, etc., often accompanied by metabolic syndromes such as infertility, obesity, insulin resistance, and dyslipidemia. It is also a key factor in the development of pregnancy complications, diabetes, cardiovascular disease, and endometrial cancer [77, 78]. Despite the increasing incidence of PCOS, its etiology is not specifically documented.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResearch has found that the relative expression of BIP mRNA and protein was significantly higher in the PCOS observation group than in the control group; similarly, the relative expression of CHOP mRNA and protein tended to be higher in the PCOS observation group than in the control group, although there was no significant difference [79]. The result several genes involved in UPR\u003csup\u003eer\u003c/sup\u003e and UPR\u003csup\u003emt\u003c/sup\u003e were overexpressed in the GCs of PCOS-IR. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR [80]. The expression of the ER stress markers GRP78, CHOP and XBP1s in the cumulus cells was higher in PCOS patients than in control patients, as were the levels of the UPR sensor proteins p-IRE1\u0026alpha;, p-EIF2\u0026alpha; and GRP78 [81]. ER stress triggers insulin resistance, and IR is the pathological basis of PCOS [82, 83]. Studies have shown that the reduction of granulosa cells in PCOS ovaries may be related to their apoptosis [84], although the exact molecular mechanism of granulosa cell-induced follicular atresia is not yet clear. Although research is still focused on the death ligand/receptor-dependent and mitochondria-dependent apoptotic pathways, the ER stress mediated apoptotic pathway in granulosa cells has also attracted increasing attention in recent years.\u0026nbsp;Sigma-1 receptor is involved in diminished ovarian reserve possibly by influencing endoplasmic reticulum stress-mediated granulosa cells apoptosis [85]. ER stress mediated granulocyte apoptosis might contribute to the pathogenesis of PCOS. PCOS ovarian granulosa cells have multi-signaling molecule anomalies, such as the abnormal expression of insulin receptors \u0026alpha; and \u0026beta; and their receptor substrate-1, decreased activity of insulin receptor, insulin receptor substrate 1 [86], and phosphatidylinositol 3-kinase in patients with PCOS, and decreased expression of glucose transporter protein 4, resulting in the occurrence of IR and decreased glucose uptake. ER stress is hypothesized to affect the apoptosis of granulosa cells by causing IR. Granulosa cells are protected by the upregulated expression of BIP within them. However, the CHOP-dependent apoptotic pathway is not yet activated, thus allowing the granulosa cells to persist, resulting in many antral follicles in patients with PCOS.\u003c/p\u003e\n\u003cp\u003ePrevious studies have shown that aerobic exercise and curcumin improve follicular dysfunction in PCOS by inhibiting the IRE1\u0026alpha;-XBP1 pathway of ER stress, and exercise-induced modulation of secreted myokine irisin improves follicular insufficiency in PCOS by inhibiting granulosa cell apoptosis through the IRE1\u0026alpha;/thioredoxin interacting protein (TXNIP) axis of ER stress [74, 75]. However, exercise recommendations are vague and, therefore, difficult to implement owing to the lack of data on the type, intensity, or duration of exercise that produces benefits for women with PCOS. Well-designed trials are needed to guide the clinical management of PCOS in women of reproductive age. The focus should be on the role of exercise therapy in the prevention of PCOS to help develop individualized, appropriate types and intensities of exercise, and targeted exercise prescriptions to prevent the disease.\u003c/p\u003e\n\u003cp\u003e2.5 Endometriosis\u003c/p\u003e\n\u003cp\u003eEndometriosis (EMT) is a benign estrogen-dependent disease associated with pelvic pain and infertility, characterized by the ectopic distribution of endometrial tissue, mainly in the pelvic peritoneum and ovaries [87]. Currently, in patients with EMs, progestin resistance is an emerging feature of the disease, in addition to estrogen dependence. EMT is a chronic disease defined as a \u0026quot;benign cancer\u0026quot; requiring lifelong management, and despite its high prevalence, treatment outcomes have been unsatisfactory owing to the complexity of its pathogenesis and the diversity of its symptoms, making it a hot topic in gynecologic research [88]. Recent studies have shown that the occurrence of EMT is associated with abnormal apoptosis [89, 90], and ER stress mediated apoptosis is one of the important pathways.\u003c/p\u003e\n\u003cp\u003eThe expression of phosphoinositide-kinase/protein kinase B (P13K/AKT) and GRP78 was shown to be significantly higher in ectopic endometrial lesion tissues than in normal endometrial tissues [91, 92]. High P13K/AKT pathway expression is one of the important mechanisms of ectopic endometrial mesenchymal cell migration. ER stress acts in cooperation with the P13K/AKT signaling pathway and is jointly involved in EMT pathogenesis [93]. Research has found that excessive reactive oxygen species induces senescence of endometriosis granular cells via arouse ER stress, which finally contributes to endometriosis-associated infertility, and melatonin may represent a novel adjuvant therapy strategy for endometriosis-associated infertility [94]. In addition, the mRNA and protein expression levels of GRP78, GRP94, caspase-12, and caspase-3 were also significantly lower in the proliferative and secretory ectopic endometrium of patients with EMT than in eutopic endometrium, this indicated that the ER stress mediated apoptotic pathway was more significantly downregulated in ectopic endometrium. Therapeutic induction of ER stress in endometriotic cells could promote apoptosis and contribute to the management of disease [95-97]. Therefore, novel therapeutic agents that focus on targeting ER stress induction may be an effective way to treat EMT.\u003c/p\u003e\n\u003cp\u003eExercise plays a significant role in the treatment and prevention of EMT [98-100], and studies have shown that exercise is beneficial in reducing the intensity of pelvic pain, controlling stress levels, and improving psychological well-being in patients with EMT, thus improving the quality of life. Regular, low-intensity aerobic exercise is beneficial in reducing the intensity of the pain in endometriosis and the size of the uterus. Exercise is beneficial in reducing the risk of developing infertility in EMT by increasing the levels of associated endocrine factors and alpha-amylase. Exercise is also beneficial in reducing the risk of EMT by shrinking EMT lesions through fatty acid synthase, matrix metalloproteinase-9, changes in proliferating cell nuclear antigen protein expression, and lowering serum testosterone levels. ER stress mediated downregulation of apoptotic pathways may be one of the important mechanisms of EMT pathogenesis, which provides important clues for the in-depth study of the exact mechanism of EMT pathogenesis. Exercise modulates ER stress induced autophagy and apoptosis. In addition, exercise can inhibit inflammatory responses, oxidative stress, angiogenesis, and dysregulation of apoptosis. These are the underlying pathophysiological triggers that lead to EMT. Therefore, finding the proper prescription exercise, developing individualized exercise programs, and exploring targeted anti-over-ER stress, anti-inflammatory, antioxidant, anti-angiogenic, and apoptotic modulators are strategies and approaches to treat EMT disease.\u003c/p\u003e"},{"header":"Conclusion and outlook","content":"\u003cp\u003eIn summary, the ER stress process is complex and plays an important role in common female diseases. The study of ER stress and UPR has led to the elucidation of the role of the ER as a \u0026quot;third interface\u0026quot; for cell signaling alongside the cell membrane and nucleus. ER stress is very closely associated with several aging-related diseases, including neurodegenerative, inflammatory, and metabolic diseases and tumors. Exercise, as a convenient and non-invasive means of health promotion, effectively modulates and ameliorates ER stress related pathologies through the corresponding molecular mechanisms. Currently, there are no clear conclusions about the effects of different exercise modalities, intensity, and duration on ER stress intensity and stress duration in different tissues. Therefore, exploring the effects of different exercise modalities on different levels of ER stress disease remains a hot topic of research in the field of health and biomedicine. Exploring the role of the exercise-ER stress-autophagy pathway in regulating the survival of common gynecologic tumor cells provides a new theoretical basis for tumor treatment. However, many aspects of ER stress are still unknown. With the progressive study of the regulatory mechanisms of ER stress and UPR signaling pathways and molecules, IRE1-XBP1, PERK, and ATF-6, further understanding of the mechanisms of development of common gynecological diseases at the cellular and molecular levels, by activating or inhibiting these pathways, may be beneficial for the treatment of relevant diseases. The scientific exercise program may provide new strategies for immunotherapy in women\u0026apos;s health.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Research Foundation for Youth Scholars of Jiaxing University (00323023AL and CD70522025).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDC,SS, LC and JZ wrote the draft. YZ, SZ and YW revised the text. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that this editorial was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJonas Bloch Thorlund, Milena Simic, Kenneth Pihl, et al. Similar Effects of Exercise Therapy, Nonsteroidal Anti-inflammatory Drugs, and Opioids for Knee Osteoarthritis Pain: A Systematic Review with Network Meta-analysis[J]. \u003cem\u003eJ Orthop Sports Phys Ther\u003c/em\u003e, 2022, 52(4):207-216.\u003c/li\u003e\n\u003cli\u003eJonathan M Memme, Avigail T Erlich, Geetika Phukan, et al. Exercise and mitochondrial health[J]. \u003cem\u003eJ Physiol\u003c/em\u003e, 2021, 599(3):803-817.\u003c/li\u003e\n\u003cli\u003eShengqi He, Tingting Fu, Yue Yu, et al. IRE1\u0026alpha; regulates skeletal muscle regeneration through Myostatin mRNA decay[J]. \u003cem\u003eJ Clin Invest\u003c/em\u003e, 2021, 131(17): e143737.\u003c/li\u003e\n\u003cli\u003eIng-Shiow Lay, Wei-Wen Kuo, Marthandam Asokan Shibu, et al. Exercise training restores IGFIR survival signaling in d-galactose induced-aging rats to suppress cardiac apoptosis[J]. \u003cem\u003eJ Adv Res\u003c/em\u003e, 2020, 28:35-41.\u003c/li\u003e\n\u003cli\u003eCorey R.Hart, Zachary C.Ryan, Kyle T Pfaffenbach, et al. Attenuated activation of the unfolded protein response following exercise in skeletal muscle of older adults[J]. \u003cem\u003eAging (Albany NY)\u003c/em\u003e, 2019, 11(18): 7587-7604.\u003c/li\u003e\n\u003cli\u003eFengwu Li, Xiaokun Geng, Hangil Lee, et al. Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress[J]. \u003cem\u003eFront Cell Neurosci\u003c/em\u003e. 2021, 15: 598230.\u003c/li\u003e\n\u003cli\u003eTakashi Yamada, Yuki Ashida, Katsuyuki Tamai, et al. Improved skeletal muscle fatigue resistance in experimental autoimmune myositis mice following high-intensity interval training[J]. \u003cem\u003eArthritis Res Ther\u003c/em\u003e. 2022, 24(1): 156.\u003c/li\u003e\n\u003cli\u003eYuan Zhang, Yuting Liu , Xiaowei Liu, et al. Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice[J]. \u003cem\u003eOxid Med Cell Longev\u003c/em\u003e. 2022, 2022: 2297268.\u003c/li\u003e\n\u003cli\u003eGuangqi Wang , Fengjuan Fan, Chunyan Sun, et al. Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?[J].\u003cem\u003e Cancers (Basel)\u003c/em\u003e, 2022, 14(21):5340.\u003c/li\u003e\n\u003cli\u003eZe Liu, Guanlin Liu, Dat P Ha, et al. ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator[J]. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e. 2023, 120(31): e2303448120.\u003c/li\u003e\n\u003cli\u003eJun Ren, Yaguang Bi, James R Sowers, et al. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases[J]. \u003cem\u003eNat Rev Cardiol\u003c/em\u003e, 202, 18(7): 499-521.\u003c/li\u003e\n\u003cli\u003eMegan C Kopp, Natacha Larburu, Vinoth Durairaj, et al. UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor[J]. \u003cem\u003eNat Struct Mol Biol\u003c/em\u003e. 2019, 26(11): 1053-1062.\u003c/li\u003e\n\u003cli\u003eHai Hu, Mingxing Tian, Chan Ding, et al. The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection[J]. \u003cem\u003eFront Immunol\u003c/em\u003e, 2019, 9: 3083.\u003c/li\u003e\n\u003cli\u003eYiming Li, Yunshan Guo, Juan Tang, et al. New insights into the roles of CHOP-induced apoptosis in ER stress[J].\u003cem\u003e Acta Biochim Biophys Sin (Shanghai)\u003c/em\u003e. 2014, 46(8): 629-40.\u003c/li\u003e\n\u003cli\u003eXudan Liu, Yao Chen, Huanhuan Wang, et al. Microglia-derived IL-1\u0026beta; promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK/eIF2\u0026alpha;/ATF4/CHOP upon arsenic exposure[J]. \u003cem\u003eJ Hazard Mater\u003c/em\u003e. 2021, 417: 125997.\u003c/li\u003e\n\u003cli\u003eStephan Mueller, Ephraim B Winzer, Andr\u0026eacute; Duvinage, et al. Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial[J]. \u003cem\u003eJAMA\u003c/em\u003e, 2021, 325(6): 542-551.\u003c/li\u003e\n\u003cli\u003eYuxiao Liao, Zhao Peng, Liangkai Chen, et al. Prospective Views for Whey Protein and/or Resistance Training Against Age-related Sarcopenia[J]\u003cstrong\u003e.\u003c/strong\u003e \u003cem\u003eAging Dis\u003c/em\u003e, 2019,10(1)；157-173.\u003c/li\u003e\n\u003cli\u003eLeslie A. Consitt, Courtney Dudley, Gunjan Saxena.\u003cstrong\u003e \u003c/strong\u003eImpact of Endurance and Resistance Training on Skeletal Muscle Glucose Metabolism in Older Adults[J]. \u003cem\u003eNutrients\u003c/em\u003e, 2019, 11(11): 2636.\u003c/li\u003e\n\u003cli\u003eAntonella Muscella, Erika Stef\u0026agrave;no, Santo Marsigliante. The effects of exercise training on lipid metabolism and coronary heart disease[J]. \u003cem\u003eAm J Physiol Heart Circ Physiol\u003c/em\u003e, 2020, 319(1): H76-H88. \u003c/li\u003e\n\u003cli\u003eSeyedeh Hoda Seyedizadeh, Sadegh Cheragh-Birjandi, Mohammad Reza Hamedi Nia. The Effects of Combined Exercise Training (Resistance-Aerobic) on Serum Kinesin and Physical Function in Type 2 Diabetes Patients with Diabetic Peripheral Neuropathy (Randomized Controlled Trials) [J]. \u003cem\u003eJ Diabetes Res\u003c/em\u003e, 2020, 2020: 6978128.\u003c/li\u003e\n\u003cli\u003eSoo LS，Ho YJ，Seok SY. Effect of the low- versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus[J]. \u003cem\u003eJ Phys Ther Sci\u003c/em\u003e, 2015, 27(10): 3063-3068.\u003c/li\u003e\n\u003cli\u003eBrisamar Est\u0026eacute;banez, Jos\u0026eacute; A de Paz, Mar\u0026iacute;a J Cuevas, et al. Endoplasmic Reticulum Unfolded Protein Response, Aging and Exercise: An Update[J]. \u003cem\u003eFront Physiol\u003c/em\u003e, 2018, 9:1744.\u003c/li\u003e\n\u003cli\u003eEmanuel Passos, Cid\u0026aacute;lia Pereira, In\u0026ecirc;s O Gon\u0026ccedil;alves, et al. Physical exercise positively modulates nonalcoholic steatohepatitis-related hepatic endoplasmic reticulum stress[J]. \u003cem\u003eJ Cell Biochem\u003c/em\u003e, 2022, 123(10): 1647-1662.\u003c/li\u003e\n\u003cli\u003eBozi LH, Jannig PR, Rolim N, et al. Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats[J]. \u003cem\u003eJ Cell Mol Med\u003c/em\u003e, 2016, 20(11): 2208-2212.\u003c/li\u003e\n\u003cli\u003eBruno B Marafon, Ana P Pinto, Eduardo R Ropelle, et al. Muscle endoplasmic reticulum stress in exercise[J]. \u003cem\u003eActa Physiol (Oxf)\u003c/em\u003e, 2022, 235(1): e13799.\u003c/li\u003e\n\u003cli\u003eMatheus Santos de Sousa Fernandes, Georgian Badicu, Gabriela Carvalho Jurema Santos, et al. Physical Exercise Decreases Endoplasmic Reticulum Stress in Central and Peripheral Tissues of Rodents: A Systematic Review[J]. \u003cem\u003eEur J Investig Health Psychol Educ\u003c/em\u003e, 2023, 13(6): 1082-1096.\u003c/li\u003e\n\u003cli\u003eLi F, Liu BB, Cai M, et al. Excessive endoplasmic reticulum stress and decreased neuroplasticity-associated proteins in prefrontal cortex of obese rats and the regulatory effects of aerobic exercise[J]. \u003cem\u003eBrain Res Bull\u003c/em\u003e, 2018, 140: 52-59.\u003c/li\u003e\n\u003cli\u003eLing Ruan, Fanghui Li, Shoubang Li, et al. Effect of Different Exercise Intensities on Hepatocyte Apoptosis in HFD-Induced NAFLD in Rats: The Possible Role of Endoplasmic Reticulum Stress through the Regulation of the IRE1/JNK and eIF2 \u0026alpha;/CHOP Signal Pathways[J]. \u003cem\u003eOxid Med Cell Longev\u003c/em\u003e. 2021, 2021: 6378568. \u003c/li\u003e\n\u003cli\u003ePontus Bostr\u0026ouml;m, Jun Wu, Mark P Jedrychowski, et al. A PGC1-\u0026alpha;-dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis[J]. \u003cem\u003eNature\u003c/em\u003e, 2012, 481(7382):463-468.\u003c/li\u003e\n\u003cli\u003eJyotirmaya Behera, Jessica Ison, Michael J Voor, et al. Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis[J]. \u003cem\u003eDiabetes\u003c/em\u003e, 2022, 71(12): 2777-2792. \u003c/li\u003e\n\u003cli\u003eWu J, Ruas JL, Estall JL, et al. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC- 1\u0026alpha;/ATF6\u0026alpha; complex[J]. \u003cem\u003eCell Metab\u003c/em\u003e, 2011, 13(2):160-169.\u003c/li\u003e\n\u003cli\u003eKhadir A, Kavalakatt S, Abubaker J, et al. Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone[J]. \u003cem\u003eMetabolism\u003c/em\u003e，2016, 659(9): 1409-1420.\u003c/li\u003e\n\u003cli\u003eKim K, Ahn N, Jung S, et al. Effects of intermittent ladder-climbing exercise training on mitochondrial biogenesis and endoplasmic reticulum stress of the cardiac muscle in obese middle-aged rats[J]. \u003cem\u003eKorean J Physiol Pharmacol\u003c/em\u003e, 2017, 21(6): 633-641.\u003c/li\u003e\n\u003cli\u003eBohnert KR, Mcmillan JD, Kumar A. Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease[J]. \u003cem\u003eJ Cell Physiol\u003c/em\u003e, 2018, 233: 67-78.\u003c/li\u003e\n\u003cli\u003eBruno B Marafon, Ana P Pinto, Eduardo R Ropelle, et al. Muscle endoplasmic reticulum stress in exercise[J]. Acta Physiol (Oxf). 2022, 235(1): e13799.\u003c/li\u003e\n\u003cli\u003eRebecca H Johnson, Carey K Anders, Jennifer K Litton, et al. Breast Cancer in Adolescents and Young Adults[J]. \u003cem\u003ePediatr Blood Cancer\u003c/em\u003e, 2018, 65(12): e27397.\u003c/li\u003e\n\u003cli\u003eC Sessa, J Balma\u0026ntilde;a, S L Bober, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline[J]. \u003cem\u003eAnn Oncol\u003c/em\u003e, 2023, 34(1): 33-47.\u003c/li\u003e\n\u003cli\u003eAlison Laws, Rinaa S Punglia. Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer[J].\u003cem\u003e J Clin Oncol\u003c/em\u003e, 2023, 41(17): 3092-3099.\u003c/li\u003e\n\u003cli\u003eAnna Kawiak. Molecular Research and Treatment of Breast Cancer[J].\u003cem\u003e Int J Mol Sci\u003c/em\u003e, 2022, 23(17):9617.\u003c/li\u003e\n\u003cli\u003eZHU Pei，LIU Ya-kun，JIANG Yu, et al. Ethanol promotes the progression of breast cancer in mice by activating endoplasmic reticulum stress[J]. \u003cem\u003eACTA LABO\u003c/em\u003e\u003cem\u003eＲ\u003c/em\u003e\u003cem\u003eATO\u003c/em\u003e\u003cem\u003eＲ\u003c/em\u003e\u003cem\u003eIUM ANIMALIS SCIENTIA SINICA\u003c/em\u003e, 2017, 25(6): 605-610.\u003c/li\u003e\n\u003cli\u003eTzu-Jung Yu, Jun-Ping Shiau, Jen-Yang Tang, et al. Physapruin A Exerts Endoplasmic Reticulum Stress to Trigger Breast Cancer Cell Apoptosis via Oxidative Stress[J]. \u003cem\u003eInt J Mol Sci,\u003c/em\u003e 2023, 24(10): 8853.\u003c/li\u003e\n\u003cli\u003eYujin Jin, Diem Thi Ngoc Huynh, Kyung-Sun Heo. Ginsenoside Rh1 inhibits tumor growth in MDA-MB-231 breast cancer cells via mitochondrial ROS and ER stress-mediated signaling pathway. \u003cem\u003eArch Pharm Res\u003c/em\u003e. 2022, 45(3): 174-184.\u003c/li\u003e\n\u003cli\u003eJes\u0026uacute;s E Serrano-Negr\u0026oacute;n, Zhenbo Zhang, Andrea P Rivera-Ruiz, et al. Tunicamycin-induced ER stress in breast cancer cells neither expresses GRP78 on the surface nor secretes it into the media[J]. \u003cem\u003eGlycobiology\u003c/em\u003e. 2018, 28(2): 61-68.\u003c/li\u003e\n\u003cli\u003eTao SS, Chen L. Role of a novel endoplasmic reticulum stress-inducible protein TRIM25 in breast cancer cells[J]. \u003cem\u003eJournal of Integration Technology\u003c/em\u003e, 2020, 9(1): 45-54.\u003c/li\u003e\n\u003cli\u003eWeixi Jiang, Li Chen, Xun Guo, et al. Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy[J]. \u003cem\u003eTheranostics\u003c/em\u003e. 2022, 12(6): 2987-3006.\u003c/li\u003e\n\u003cli\u003eYifeng Zheng, Pengxi Liu, Neng Wang, et al. Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway[J]. \u003cem\u003eOxid Med Cell Longev\u003c/em\u003e. 2019, 2019: 8781690.\u003c/li\u003e\n\u003cli\u003eSeo Yeon Lee, Tae Hoon Kim, Won Geun Choi, et al. SH003 Causes ER Stress-mediated Apoptosis of Breast Cancer Cells via Intracellular ROS Production[J]. \u003cem\u003eCancer Genomics Proteomics\u003c/em\u003e. 2023, 20(1): 88-116.\u003c/li\u003e\n\u003cli\u003eHalima Alsamri, Aysha Alneyadi, Khalid Muhammad, et al. Carnosol Induces p38-Mediated ER Stress Response and Autophagy in Human Breast Cancer Cells[J]. \u003cem\u003eFront Oncol\u003c/em\u003e. 2022, 12:911615.\u003c/li\u003e\n\u003cli\u003eWenyu Ma. Berberine and regular exercise synergetically inhibit the progression of breast cancer by mediating SCFAs and immune regulation[J]. Southwest University, 2021. 1: 1-81.\u003c/li\u003e\n\u003cli\u003eAntonieta Alvarado, Rui M Gil da Costa, Ana I Faustino-Rocha. Effects of exercise training on breast cancer metastasis in a rat model[J]. \u003cem\u003eInt J Exp Pathol\u003c/em\u003e. 2017, 98(1): 40-46.\u003c/li\u003e\n\u003cli\u003eHuiying Ma, Tian Tian, Zhumei Cui. Targeting ovarian cancer stem cells: a new way out[J]. \u003cem\u003eStem Cell Res Ther\u003c/em\u003e, 2023, 14(1): 28.\u003c/li\u003e\n\u003cli\u003eRuiqian Zhang, Michelle K Y Siu, Hextan Y S Ngan, et al. Molecular Biomarkers for the Early Detection of Ovarian Cancer[J]. \u003cem\u003eInt J Mol Sci\u003c/em\u003e. 2022, 23(19):12041.\u003c/li\u003e\n\u003cli\u003eHui-Di Zhang , Jian-Ni Huang, Yun-Zi Liu, et al. Endoplasmic Reticulum Stress and Proteasome Pathway Involvement in Human Podocyte Injury With a Truncated COL4A3 Mutation[J]. \u003cem\u003eChin Med J (Engl)\u003c/em\u003e. 2019, 132(15):1823-1832.\u003c/li\u003e\n\u003cli\u003eJiahang Mo, Shunyi Ruan, Baicai Yang, et al. A novel defined risk signature of endoplasmic reticulum stress-related genes for predicting the prognosis and immune infiltration status of ovarian cancer[J]. \u003cem\u003eJ Zhejiang Univ Sci B\u003c/em\u003e. 2023, 24(1): 64-77.\u003c/li\u003e\n\u003cli\u003eEntaz Bahar, Ji-Ye Kim, Dong-Chul Kim, et al. Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway[J]. \u003cem\u003eInt J Mol Sci\u003c/em\u003e, 2021, 22(8): 3916.\u003c/li\u003e\n\u003cli\u003eXueping Chen, Zhiqiang Zha, Yu Wang, et al. Knockdown of ENTPD5 inhibits tumor metastasis and growth via regulating the GRP78/p-eIF-2\u0026alpha;/CHOP pathway in serous ovarian cancer[J]. \u003cem\u003eJ Ovarian Res\u003c/em\u003e, 2022, 15(1): 69. \u003c/li\u003e\n\u003cli\u003eXiao Zhenghong, Xie Guanglun, Zhai Huange, et al. Silent Galectin-3 induces apoptosis and endoplasmic reticulum stress in ovarian cancer cells in invitro[J]. Modern Oncology, 2020, 28 (10): 1638-1642.\u003c/li\u003e\n\u003cli\u003eGuangyuan Zhao, Yuying Tan, Horacio Cardenas, et al. Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids[J]. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e. 2022, 119(41): e2203480119.\u003c/li\u003e\n\u003cli\u003eShekufe Rezghi Barez, Ahmad Movahedian Attar, Mahmoud Aghaei. MicroRNA-30c-2-3p regulates ER stress and induces apoptosis in ovarian cancer cells underlying ER stress[J]. EXCLI J. 2021, 20: 922-934. \u003c/li\u003e\n\u003cli\u003eZHANG Jia-ling, ZHENG Chuan-jun, YAN Rui-qi, et al. Apoptosis of ovarian cancer cells induced by polyphyllin VII and cisplatin through endoplasmic reticulum stress[J]. \u003cem\u003eChin J Lab Diagn\u003c/em\u003e, 2015, 19(1): 6-9.\u003c/li\u003e\n\u003cli\u003eQiu Xijian, Huang Yiwu, Xu Meihu. Effect of Qizaoyixue decoction with exercise on cancer-related fatigue for oophoroma patients duringintermittent chemotherapy[J]. \u003cem\u003eModern Nursing\u003c/em\u003e，2011, 14: 1646-1649.\u003c/li\u003e\n\u003cli\u003eSuzanne C Dixon-Suen, Sarah J Lewis, Richard M Martin, et al. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study[J]. \u003cem\u003eBr J Sports Med\u003c/em\u003e. 2022, 56(20): 1157-1170.\u003c/li\u003e\n\u003cli\u003eLisa Rahangdale, Chemtai Mungo, Siobhan O\u0026apos;Connor, et al. Human papillomavirus vaccination and cervical cancer risk[J]. \u003cem\u003eBMJ\u003c/em\u003e, 2022, 379: e070115.\u003c/li\u003e\n\u003cli\u003eArvind Krishnamurthy, Vijayalakshmi Ramshankar. Current Status and Future Perspectives of Molecular Prevention Strategies for Cervical Cancers[J]. \u003cem\u003eIndian J Surg Oncol\u003c/em\u003e, 2020, 11(4): 752-761.\u003c/li\u003e\n\u003cli\u003eHaowen Dou, Shasha Yang, Yulai Hu, et al. Sesamin induces ER stress-mediated apoptosis and activates autophagy in cervical cancer cells[J]. \u003cem\u003eLife Sci\u003c/em\u003e. 2018, 200: 87-93.\u003c/li\u003e\n\u003cli\u003eBoyun Kim, Hee Seung Kim, Eun-Ji Jung, et al. Curcumin induces ER stress-mediated apoptosis through selective generation of reactive oxygen species in cervical cancer cells[J]. \u003cem\u003eMol Carcinog\u003c/em\u003e. 2016, 55(5): 918-928. \u003c/li\u003e\n\u003cli\u003eXiu-Mei Li, Jing Liu, Fang-Fang Pan, et al. Quercetin and aconitine synergistically induces the human cervical carcinoma HeLa cell apoptosis via endoplasmic reticulum (ER) stress pathway[J]. \u003cem\u003ePLoS One\u003c/em\u003e. 2018, 13(1): e0191062.\u003c/li\u003e\n\u003cli\u003eRen Songjie, Lv Juan, Li Jiang, et al. Effect of endoplasmic reticulum-related degradation protein Derlin-1 on autophagy pathway of cervical cancer C33A cells[J]. \u003cem\u003eJ Shanxi Med Univ\u003c/em\u003e, 2020, 51(3): 198-202.\u003c/li\u003e\n\u003cli\u003eZhijia Li, Muzhou Teng, Yajie Wang, et al. The mechanism of 5-aminolevulinic acid photodynamic therapy in promoting endoplasmic reticulum stress in the treatment of HR-HPV-infected HeLa cells[J]. \u003cem\u003ePhotodermatol Photoimmunol Photomed\u003c/em\u003e. 2021, 37(4):348-359. \u003c/li\u003e\n\u003cli\u003eBing Han, Hongbo Wang, Jianzhao Zhang. FNDC3B Is Associated with ER Stress and Poor Prognosis in Cervical Cancer[J]. \u003cem\u003eOncol Lett\u003c/em\u003e. 2020, 19(1): 406-414.\u003c/li\u003e\n\u003cli\u003eXue Liu, Jing Song, Hui Liu, et al. Endoplasmic Reticulum Stress Could Predict the Prognosis of Cervical Cancer and Regulate the Occurrence of Radiation Mucositis[J]. \u003cem\u003eDose Response\u003c/em\u003e. 2023, 21(2):15593258231173199.\u003c/li\u003e\n\u003cli\u003eJagoda Adamczyk-Grochala, Dominika Bloniarz, Klaudia Zielinska, et al. DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis[J]. \u003cem\u003eApoptosis\u003c/em\u003e. 2023, 28(1-2):166-185.\u003c/li\u003e\n\u003cli\u003eBING Qing. Expression and clinical significance of AMF in cervical cancer[J]. \u003cem\u003eJournal of China Prescription Drug\u003c/em\u003e. 2021, 19(05). \u003c/li\u003e\n\u003cli\u003eYaling Zhang, Yajing Weng, Daojuan Wang, et al. Curcumin in combination with aerobic exercise improves follicular dysfunction via inhibition of the hyperandrogen-induced IRE1\u0026alpha;/XBP1 endoplasmic reticulum stress pathway in PCOS-like rats[J]. \u003cem\u003eOxidative Medicine and Cellular Longevity\u003c/em\u003e. 2021, 2021:7382900.\u003c/li\u003e\n\u003cli\u003eYajing Weng, Yaling Zhang, Daojuan Wang, et al. Exercise-induced Irisin improves follicular dysfunction by inhibiting IRE1\u0026alpha;-TXNIP/ROS-NLRP3 pathway in PCOS[J]. \u003cem\u003eJ Ovarian Res\u003c/em\u003e. 2023, 16(1): 151.\u003c/li\u003e\n\u003cli\u003eHeather G Huddleston 1, Anuja Dokras . Diagnosis and Treatment of Polycystic Ovary Syndrome[J]. \u003cem\u003eJAMA\u003c/em\u003e, 2022, 327(3): 274-275.\u003c/li\u003e\n\u003cli\u003eDumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome[J]. \u003cem\u003eEndocrine Reviews\u003c/em\u003e. 2015, 36:487-525.\u003c/li\u003e\n\u003cli\u003eElisabet Stener-Victorin 1, Qiaolin Deng. Transmission of Polycystic Ovary Syndrome via Epigenetic Inheritance[J]. \u003cem\u003eTrends Mol Med\u003c/em\u003e, 2021, 27(8):723-724.\u003c/li\u003e\n\u003cli\u003eHiroshi Koike, Miyuki Harada, Akari Kusamoto, et al. Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome[J]. \u003cem\u003eFront Endocrinol (Lausanne)\u003c/em\u003e, 2023, 14: 1124405.\u003c/li\u003e\n\u003cli\u003eMauro Cozzolino, Sonia Herraiz, Yigit Cakiroglu, et al. Distress response in granulosa cells of women affected by PCOS with or without insulin resistance[J]. \u003cem\u003eEndocrine\u003c/em\u003e. 2023, 79(1): 200-207. \u003c/li\u003e\n\u003cli\u003eJiamin Jin, Yerong Ma, Xiaomei Tong, et al. Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK[J]. \u003cem\u003eHum Reprod\u003c/em\u003e. 2020, 35(5): 1145-1158.\u003c/li\u003e\n\u003cli\u003eChantal Anifa Amisi. Markers of insulin resistance in Polycystic ovary syndrome women: An update[J]. \u003cem\u003eWorld J Diabetes\u003c/em\u003e, 2022, 13(3):129-149.\u003c/li\u003e\n\u003cli\u003eYan Peng, Liyuan Guo, Anxin Gu, et al. Electroacupuncture alleviates polycystic ovary syndrome-like symptoms through improving insulin resistance, mitochondrial dysfunction, and endoplasmic reticulum stress via enhancing autophagy in rats[J]. \u003cem\u003eMol Med\u003c/em\u003e, 2020, 26(1):73.\u003c/li\u003e\n\u003cli\u003eJerilee M K Azhary, Miyuki Harada, Nozomi Takahashi. Endoplasmic Reticulum Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS[J]. \u003cem\u003eEndocrinology\u003c/em\u003e. 2019, 160(1): 119-132.\u003c/li\u003e\n\u003cli\u003eLile Jiang, Jinquan Cui, Cuilian Zhang, et al. Sigma-1 receptor is involved in diminished ovarian reserve possibly by influencing endoplasmic reticulum stress-mediated granulosa cells apoptosis[J]. \u003cem\u003eAging (Albany NY)\u003c/em\u003e, 2020, 12(10): 9041-9065.\u003c/li\u003e\n\u003cli\u003eBojana Mićić, Ana Djordjevic, Nata\u0026scaron;a Veličković，et al. AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding[J]. \u003cem\u003eBiomedicines\u003c/em\u003e, 2023, 11(6): 1586.\u003c/li\u003e\n\u003cli\u003ePatricia Ribeiro de Carvalho Fran\u0026ccedil;a, Anna Carolina Pereira Lontra, Patricia Dias Fernandes. Endometriosis: A Disease with Few Direct Treatment Options[J]. \u003cem\u003eMolecules\u003c/em\u003e. 2022, 27(13): 4034.\u003c/li\u003e\n\u003cli\u003eAndrew W Horne, Stacey A Missmer. Pathophysiology, diagnosis, and management of endometriosis[J].\u003cem\u003e BMJ\u003c/em\u003e, 2022, 379: e070750.\u003c/li\u003e\n\u003cli\u003eSudipta Dutta, Sakhila K Banu, Joe A Arosh. Endocrine disruptors and endometriosis[J]. \u003cem\u003eReprod Toxicol\u003c/em\u003e, 2023, 115:56-73.\u003c/li\u003e\n\u003cli\u003eElif Bilgic , Elif Guzel , Sevil Kose, et al. Endocannabinoids Modulate Apoptosis in Endometriosis and Adenomyosis[J]. \u003cem\u003eActa Histochem\u003c/em\u003e, 2017, 119(5):523-532.\u003c/li\u003e\n\u003cli\u003eLama Assaf, Assaad A Eid, Joseph Nassif. Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis[J]. \u003cem\u003eLife Sci\u003c/em\u003e. 2022, 306: 120805.\u003c/li\u003e\n\u003cli\u003eJongYeob Choi, MinWha Jo, EunYoung Lee, et al. Nuclear factor-kappa B signaling in endometriotic stromal cells is not inhibited by progesterone owing to an aberrant endoplasmic reticulum stress response: a possible role for an altered inflammatory process in endometriosis[J]. \u003cem\u003eMol Hum Reprod\u003c/em\u003e, 2021, 27(2): gaab002.\u003c/li\u003e\n\u003cli\u003ePark S, Lim W, Bazer FW, et al. Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells[J]. \u003cem\u003eJ Cell Physiol\u003c/em\u003e, 2018, 233(4): 3055-3065.\u003c/li\u003e\n\u003cli\u003eXiang Lin, Yongdong Dai, Xiaomei Tong, et al. Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility[J]. \u003cem\u003eRedox Biol\u003c/em\u003e, 2020, 30:101431.\u003c/li\u003e\n\u003cli\u003eHussein Riyadh Abdul Kareem Al-Hetty, Ahmed Darweesh Jabbar, Vladimir F Eremin , et al. The role of endoplasmic reticulum stress in endometriosis[J]. \u003cem\u003eCell Stress Chaperones\u003c/em\u003e, 2023, 28(2): 145-150.\u003c/li\u003e\n\u003cli\u003eSara Hansen, Una \u0026Aacute; Sverrisd\u0026oacute;ttir, Martin Rudnicki. Impact of exercise on pain perception in women with endometriosis: A systematic review[J]. \u003cem\u003eActa Obstet Gynecol Scand\u003c/em\u003e, 2021, 100(9): 1595-1601.\u003c/li\u003e\n\u003cli\u003eChisato Kunitomi, Miyuki Harada, Nozomi Takahashi, et al. Activation of endoplasmic reticulum stress mediates oxidative stress-induced apoptosis of granulosa cells in ovaries affected by endometrioma[J]. \u003cem\u003eMol Hum Reprod\u003c/em\u003e. 2020, 26(1): 40-52.\u003c/li\u003e\n\u003cli\u003eSara Hansen, Una \u0026Aacute; Sverrisd\u0026oacute;ttir, Martin Rudnicki. Impact of exercise on pain perception in women with endometriosis: A systematic review[J]. \u003cem\u003eActa Obstet Gynecol Scand\u003c/em\u003e. 2021, 100(9): 1595-1601.\u003c/li\u003e\n\u003cli\u003eZahra Salehpoor, Bahia Namavar Jahromi, Nader Tanideh, et al. High intensity interval training is superior to moderate intensity continuous training in enhancing the anti-inflammatory and apoptotic effect of pentoxifylline in the rat model of endometriosis[J]. \u003cem\u003eJ Reprod Immunol\u003c/em\u003e. 202, 156: 103832.\u003c/li\u003e\n\u003cli\u003eJ C Rosa-E-Silva, M L Montenegro, J Meola, et al. Influence of Physical Exercise on Endometriosis Experimentally Induced in Rats[J]. \u003cem\u003eJ Minim Invasive Gynecol\u003c/em\u003e. 2015, 22(6S): S167.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Exercise, ER stress, Breast cancer, Ovarian cancer, Cervical carcinoma, Polycystic ovary syndrome","lastPublishedDoi":"10.21203/rs.3.rs-3704046/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3704046/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eExercise, as an effective non-drug intervention, plays an important role in preventing and alleviating several diseases. Endoplasmic reticulum (ER) stress is caused by an excessive accumulation of unfolded or misfolded proteins in the ER and also serves as the body\u0026rsquo;s internal self-protection mechanism. ER stress occurrence can be detected in the cells in many diseases such as cancer, diabetes, obesity, osteoporosis, neurodegenerative diseases, and metabolic diseases. In recent years, exercise has been suggested to change the molecular mechanisms related to various diseases by regulating ER stress. With increasing attention on women's health, some common diseases have also become research hotspots, such as breast, ovarian, cervical, endometrial cancer, polycystic ovary syndrome (PCOS) and endometriosis prevention and treatment; and other diseases. This manuscript reviews the relationship between exercise and ER stress and its role in common female endocrine system-related diseases.\u003c/p\u003e","manuscriptTitle":"Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-15 00:02:50","doi":"10.21203/rs.3.rs-3704046/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"04a2a2f7-d84d-4388-8a1f-a0b8687df01f","owner":[],"postedDate":"December 15th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-15T00:02:52+00:00","versionOfRecord":[],"versionCreatedAt":"2023-12-15 00:02:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3704046","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3704046","identity":"rs-3704046","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}