{"paper_id":"cbcb6fca-a7c9-47fb-a6a9-c96b32e508f7","body_text":"EM is a disease caused by functional endometrial tissues growing in other areas outside the uterine cavity. It is a chronic disease that affects productivity and quality of life in women. \n 1 \n  The typical presenting symptoms in women with EM include chronic pelvic pain, abnormal menstruation, and dyspareunia. EM occurs frequently in women of reproductive age, and the incidence is approximately 10%. \n 2 \n  Approximately 40%–60% of women with EM experience dysmenorrhea, and 20%–30% are complicated with infertility. \n 3\nAlthough EM presents as benign clinical and pathological manifestations, it has similar characteristics to cancers, including dissemination, invasion, and hyperplasia. It is generally accepted that EM is a hormone‐dependent disease. \n 4 \n  Estrogen (E 2 ) augmentation and progesterone resistance feature EM pathology, but the mechanism of how this occurs is unclear. Nevertheless, EM has been observed even in the absence of increased E 2  production in postmenopausal women. \n 5 \n  The pathogenesis of EM is dominated by the theory of ectopic implantation of the endometrium, along with multiple factors, such as endocrine, immunity, invasion, and angiogenesis. Retrograde menstruation theory suggests reflux of endometrial tissue through the fallopian tubes during menstruation and implantation into the peritoneal cavity. 6 ,  7  Lymphatic and vascular dissemination theories suggest that endometrial cells disseminate via lymphatic or blood circulation. \n 8 \n  Stem cell origin theory suggests that undifferentiated peritoneal tissue, ovarian surface epithelial tissue, and endometrium mesenchymal stem cells transform into endometrial‐like tissue in response to retrograde menstrual blood flow and stimulation from chronic inflammatory factors. \n 9\nEM development is also associated with a combination of genetic variation and environmental factors. First‐degree relatives of women with EM have a seven fold greater risk of developing EM than those without a family history, and the risk of developing the disease in identical twins of women with EM is as high as 75%. 10 ,  11  In recent years, the increased incidence of EM is also thought to be associated with exposure to environmental pollutants. Tetrachlorodibenzo‐p‐dioxin (TCDD) is the most prevalent air pollutant worldwide, and it promotes cytokine secretion. Endogenous E 2  exacerbates the effects of TCDD and the interaction of the two chemicals provokes inflammatory responses, induces toxicity, and thus increases the severity of EM. 12 ,  13 ,  14  Therefore, the pathophysiology of EM is complex, interrelated, and specific, thereby requiring multiple targeted therapies.\nRegardless of EM theories, endometrial cells must complete a serial process of immune escape, survival, adhesion, invasion, and angiogenesis to develop and grow in the ectopic sites. \n 15 \n  Signaling pathway refers to a series of enzymatic reaction pathways that pass molecular signals into cells through the cell membrane to exert corresponding effects. EM‐related signaling pathways, together with their upstream and downstream regulatory factors, constitute a large and complex transduction system and play an important role in the occurrence and development of EM. Abnormalities in these pathways and their interactions can lead to abnormal proliferation, apoptosis, autophagy, adhesion, invasion, fibrosis, angiogenesis, reactive oxidative stress (ROS), immune system, and inflammatory responses of the ectopic endometrial tissues, thereby promoting its growth and development. Hormonal‐related enzymes, growth factors, inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)‐α, transforming growth factors (TGF)‐β, prostaglandin E 2  (PGE 2 ), prostaglandin‐endoperoxide synthase (COX)2 play important roles in these processes. 16 ,  17  They induce local immune imbalance in the microenvironment to tolerate immune clearance and promote the survival of ectopic lesions. Downstream molecules, such as hypoxia‐inducible factors (HIF)‐1α, matrix metallopeptidase (MMPs), and vascular endothelial growth factors (VEGFs), are dysregulated and play roles in the angiogenesis and growth of EM lesions. 2 ,  15 ,  16 ,  17\nCurrent treatments for EM include surgical and medical therapies. Conservative surgery removes the EM deposits but increases the risk of impairing ovarian reserve, harming other organs, and imposing postoperative recurrence. \n 18 \n  Therefore, medical therapy (Table  1 ) always comes first into consideration, and the choices depend on multiple factors, such as symptom severity, conceive desire, and comorbidities. Generic classes of medical therapies for EM include hormonal therapy, including oral contraceptives (COC), progesterone and gonadotropin‐releasing hormone (GnRH) agonist and antagonist, and nonhormonal therapies such as nonsteroidal anti‐inflammatory drugs (NSAIDs).\nCurrent FDA‐approved medication for endometriosis treatment\nTolerable side effects. Cost‐effective. Combined use of progestin with ethinyl estradiol reduces adverse effects such as thromboembolism.\nTolerable side effects.\nCost‐effective.\nCombined use of progestin with ethinyl estradiol reduces adverse effects such as thromboembolism.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth. Adverse effect associated with long‐term usage such as thromboembolism and stroke. High recurrence rate after discontinuation. Risk of impaired fertility\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nAdverse effect associated with long‐term usage such as thromboembolism and stroke.\nHigh recurrence rate after discontinuation.\nRisk of impaired fertility\nAvailable in different forms of administration and in different price ranges. Intramuscular injection form of treatments avoids daily administration and reduces gastrointestinal absorption. High specificity and minimal side effects with Dienogest.\nAvailable in different forms of administration and in different price ranges.\nIntramuscular injection form of treatments avoids daily administration and reduces gastrointestinal absorption.\nHigh specificity and minimal side effects with Dienogest.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth. Adverse effect associated with long‐term usages such as reduction in bone mineral density and virginal bleeding.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nAdverse effect associated with long‐term usages such as reduction in bone mineral density and virginal bleeding.\nAvailable in different forms of administration and in different price ranges. Direct effect on endometriotic tissues. Approved add‐back therapy can reduce side effects.\nAvailable in different forms of administration and in different price ranges.\nDirect effect on endometriotic tissues.\nApproved add‐back therapy can reduce side effects.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth. Aromatase inhibitors need to be taken to prevent initial pituitary flare effect.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nAromatase inhibitors need to be taken to prevent initial pituitary flare effect.\nLong history—First approved drug for EM.\nLong history—First approved drug for EM.\nSide effects related to hyperandrogenism such as hirsutism and muscle cramps. Increased risk of ovarian cancer. Replaced by alternative agents due to adverse effects.\nSide effects related to hyperandrogenism such as hirsutism and muscle cramps.\nIncreased risk of ovarian cancer.\nReplaced by alternative agents due to adverse effects.\nLower degree of hypoestrogenism side effects compared to GnRH agonists. Flexible and rapid reversible onset and offset.\nLower degree of hypoestrogenism side effects compared to GnRH agonists.\nFlexible and rapid reversible onset and offset.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth. Adverse effect associated with long‐term usage such as reduction in bone mineral density.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nAdverse effect associated with long‐term usage such as reduction in bone mineral density.\nConvenient as one injection per month.\nConvenient as one injection per month.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth. Adverse effect associated with long‐term usage such as osteoporosis. Expensive\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nAdverse effect associated with long‐term usage such as osteoporosis.\nExpensive\nCombined use of Leuprolide with Norethindroe prevents bone thinning. Convenient as one injection per month.\nCombined use of Leuprolide with Norethindroe prevents bone thinning.\nConvenient as one injection per month.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nSide effects related to hypoestrogenism, such as hot flashes, dry vagina, nausea, headaches, and so forth.\nAbbreviations: COC, combined oral contraceptive; E 2 , estradiol; FDA, Food and Drug Administration; FSH, follicle‐stimulating hormone; GnRH, gonadotropin‐releasing hormone; LH, luteinizing hormone; LHRH, luteinizing hormone‐releasing hormone; NETA, norethindrone acetate; NSAID, nonsteroidal anti‐inflammatory drug; P4, progesterone; P450AROM, aromatase.\nData was extracted from The  Drugs.com  Database,  drugs.com .\nPrice range was justified based on 3‐months therapy. $ denotes the approximate price range and are labelled as follows, $ (<$100); $$ ($100–$499); $$$ ($500–$1999); $$$$ ($2000–$4999); $$$$$ (>$5000).\nMedication is usually prescribed together with NSAIDs.\nThe available reports on the effectiveness of NSAIDs on pain relief in EM are very limited, and there is no strong evidence to support a conclusion. \n 1 \n  Among all medical treatments, combined COC and progestin monotherapy represent the first‐line therapy, which can be applied to most women clinically diagnosed with EM with or without a surgical diagnosis. \n 26 \n  Continuous COC effectively reduces the recurrence of dysmenorrhea, \n 27 \n  and progestin suppresses ovulation by maintaining a hypoestrogenic state. Women with risk factors such as thrombosis and myocardial infarction may tolerate the side effects of progestin better than those of COC. \n 28 \n  To date, few derivatives of progesterone, namely, depot medroxyprogesterone acetate and norethindrone acetate, have been approved by the US Food and Drug Administration (FDA) as the sole therapy for EM. 29 ,  30\nAlthough GnRH is an effective hormonal treatment for EM, severe hypoestrogenic symptoms limit long‐term compliance. 31 ,  32  GnRH agonists are second‐line hormonal therapies that exert strong action on the GnRH receptor, leading to an initial short stimulation and subsequent suppression of gonadotropin secretion. Decreased hormone levels result in the dormancy of endometriotic lesions. Owing to its long‐term adverse effects, especially osteoporosis, an add‐back therapy is recommended. \n 33 \n  Recently, the FDA approved elagolix, a nonpeptide small molecule GnRH receptor antagonist that suppresses luteinizing hormone and follicle‐stimulating hormone and correspondingly reduces E 2  and progesterone, as a treatment for moderate to severe EM‐associated pain. Its efficacy was shown after a 6‐month treatment, but it also caused a significant decrease in bone mineral density as the main side effect. \n 34 \n  To overcome EM refractory to current hormonal treatments and NSAIDs, there have been extensive research of new medicines in recent years. Other than therapeutic efficacy, the potential use of a drug as a preventive treatment after surgery is also desirable. The recurrence of EM and the associated symptoms within 5 years after laparoscopy is approximately 19% in patients with endometrioma, \n 35 \n  and up to 10% of women require secondary surgery after 1 year, \n 36 \n  emphasizing the need for new medical treatments to prevent a recurrence.\nIn summary, to identify and develop new pharmaceuticals for EM treatment, understanding the dysregulated molecular and signaling pathways in EM development is essential (Figure  1 ). Numerous studies have focused on the antiproliferation mechanism and related targeted therapies in EM models and/or endometrial cells. 37 ,  38  Owing to the interaction of different signaling pathways, the efficacy of potential pharmaceuticals in promoting or inhibiting a single signaling pathway is often very limited. Therefore, pharmaceutical targeting multisignaling pathways in EM has become important in the medical treatment of EM. An overview of the molecular pathways involved in the pathophysiology of EM has been reported by various publications, 39 ,  40 ,  41  which provides a high quality evidence of the underlying pathophysiology of EM. However, previous publications only focused on currently available pharmaceuticals. In this review, we aimed to present an updated summary of studies focusing on new potential pharmaceuticals, including preclinical studies, clinical trials, as well as studies on marketed pharmaceuticals. In‐depth studies of signaling pathways targeted by pharmaceuticals are currently an emerging research direction, which will open up broad prospects for the new generation of EM treatment.\nPathophysiology of endometriosis. The schematic diagram was created using  BioRender.com . Akt, protein kinase B; ATG, autophagy‐related genes; DC, dendritic cells; E 2 , estrogen; ECM, extracellular matrix; ER, estrogen eceptor; ERK extracellular signal‐regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptors; HIF, hypoxia‐inducible factors; MΦ, macrophages; MAPK, mitogen‐activated protein kinase; MEK, ERK kinase; mTOR, mammalian target of rapamycin; NF‐κB, nuclear factor κB; NK, natural killer; PDGF, platelet‐derived growth factor; PDGFR, platelet‐derived growth factor receptor; PI3K, phosphoinositide 3‐kinases; Rho, Ras homolog family; ROCK, Rho‐associated coiled‐coil kinase; VEGF, vascular endothelial growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; Treg, regulatory T cells; Wnt, wingless‐type mouse mammary tumor virus integration site family; YAP, Yes‐associated protein\n\nThe choice of investigation models considerably influences the translational potential of preclinical research. Endometriotic and endometrial tissue cells with specific cell characteristics, defined by their morphology and phenotypes, confirmed by immunocytochemistry allow in vitro investigations of the mechanism of hormonal expression, cytokine secretion, cell proliferation, and differentiation. \n 42 \n  Romano et al. \n 43 \n  critically analyzed different EM culture models of samples from peritoneal, ovarian, and deep infiltration EM and recommended a guideline for assessing the quality of both primary endometriotic cells and immortalized endometriotic cell lines. Culture conditions can imitate EM in situ; for example, endometrium undergoing menstruation, \n 44 \n  macrophage activation, \n 45 \n  epithelium mesothelium transformation, \n 46 \n  and cell–cell interactions. 47 ,  48  In addition, in vivo animal experiments provide a biological system with an integrative environment and complete cellular and molecular network for lesion development and growth in vivo. It mimics the conditions in humans in the hopes that the results can be translated from bench to clinic. The application and limitations of various EM animal models, including autotransplantation of uterine tissues and xenotransplantation of human endometrial tissues into the peritoneal cavity or subcutaneous pocket in ectopic sites of rodent models, as well as in the primate model have been assessed, and the choice of the appropriate model for studies depends on the research questions. \n 49\nApart from the appropriate model, positive control of current pharmaceuticals should be included for comparison, which will serve as experimental evidence of the efficacy of new drugs. When choosing a positive control, pharmaceuticals with relevant actions to the examined molecular and signaling pathways should be considered. For example, dienogest can be used as a positive control to compare the inhibition of NF‐κB activation, enhancement of apoptosis, or inhibition of MMP‐2/‐9, 50 ,  51  leuprolide acetate to compare the inhibition of promitogenic cytokines, \n 52 \n  and celecoxib to compare the proliferation‐inhibitory and apoptosis‐enhancing effects. \n 53\nIn addition to the efficacy, the pharmacokinetic profile of a drug with respect to absorption, distribution, metabolism, and excretion should be available to support its clinical use. \n 54 \n  The bioavailability of a drug and its active metabolites in systematic circulation and local tissues should be quantified to justify the therapeutic dosage for clinical application. \n 55 \n  The relationship between drug potency and pharmacological effects on the body and action site should be evaluated to prevent off‐target toxicities. \n 56 \n  The possible adverse effects on other tissues also need to be determined. Medications with specific efficacy on the ectopic endometrium and minimal side effects on the eutopic endometrium are preferable for EM treatment, as these medications will affect reproductive cycles the least. In animal experiments, adverse effects on reproductive tissues and functions should be carefully monitored. As a short‐term measure, no significant change in body weight should occur in the test animals, and as a long‐term measure, the animals should be able to conceive and deliver. For women with EM who prefer symptomatic medical therapy, such side effects should be limited and well‐tolerated. Medicines that regulate E 2  levels usually result in hypoestrogenism and are associated with side effects such as hot flushes and vaginal dryness, which are acceptable, but not preferable. \n 57 \n  Other common adverse effects, such as osteoporosis and venous thromboembolism, should be avoided. The effect of the medications on fertility should also be monitored; however, the current data are very limited.\nSeveral studies have systematically recorded the direct and indirect costs of EM treatment and highlighted its long‐term economic burden on the society, healthcare system, and affected women. \n 58 \n  This has raised awareness of the disease and increased the demand for cost‐effective EM drugs. However, the choice of treatment depends not only on patients’ desired outcomes but also on treatment affordability. A cost‐effective medication is that with equivalent monetary value and efficiency. Therefore, as the most cost‐effective treatment for EM is considered for use as a standard hormonal treatment, \n 59 \n  a potential new pharmaceutical should be affordable and easily accessible to the market, in addition to showing good efficacy with fewer side effects.\nIn summary, a potential new pharmaceutical should be well‐studied in terms of not only action mechanism and efficacy  in vitro  and in vivo, but also safety, efficiency, and cost‐effectiveness. Progress in this area is expected to provide clear and effective insights for policy‐making and for decision‐making in the individualized treatment of EM.\n\nMedications investigated in ongoing or completed clinical trials on EM are summarized in Table  2 . Most drugs are mainly symptomatic. Outcome measures used in these studies are pain score, levels of dysmenorrhea and dyspareunia, and quality of life, except for epigallocatechin gallate (EGCG) and quinagolide, whose efficacy in reducing endometriotic lesions will be determined. To the best of our knowledge, there is limited clinical trial to examine the pathophysiology or signaling pathways targeted by the drugs. Moreover, heterogeneous pathophysiology among patients affects their responsiveness to drug treatment; therefore, the development of personalized medicines to specific patients based on EM pathophysiology is desirable. \n 39 \n  These further emphasizes the demand for new pharmaceutical that is for symptomatic management, as well as targets specific pathophysiology and signaling pathways to eliminate the endometriotic lesions.\nPharmaceuticals under clinical trials within 2015–2025 for endometriosis (EM) treatment a\nAll information was taken from the US National Library of Medicine,  ClinicalTrials.gov , only completed or active clinical trials, and EM treatment as the primary study purpose between 2015 and 2025 are included.\nSelected outcome measures are shown.\nHere, we discuss the pathophysiology and molecular targets that are directly or indirectly associated with the drugs, as well as their effects on the corresponding signal transduction pathways in the treatment of EM. In Table  3 , we distinguished potential drugs as a repurposed or a de novo drug of EM. A new drug is defined as a chemical that has not been studied in clinical trials for other diseases before EM and a repurposed drug is defined as a chemical that has been studied in clinical trials for other diseases before EM. We provided sufficient scientific data of their efficacies in reducing endometriotic cell viability in vitro or lesions in vivo, as well as in regulating specific signaling pathways and molecules involved in the pathophysiology of EM. The advantages, side effects, and limitations of the drugs are also highlighted.\nPathways and molecular targets of current and potential pharmaceuticals for endometriosis treatment\n↑59.1% in apoptosis (−TRAIL)\n↑1.35‐fold in apoptosis (+TRAIL) in women with EM\nAbbreviations: 17β‐hsd, 17β‐hydroxysteroid dehydrogenase; ‐SMA, ‐smooth muscle actin; AFM, atomic force microscopy; AKT, protein kinase B; P450AROM, aromatase; ASK1, apoptosis signal‐regulating kinase 1; ATF4, activating transcription factor 4; ATG, autophagy‐related protein; BRAF, serine/threonine‐protein kinase B‐Raf; CASP, caspases; CAT, catalase; CB, cannabinoid receptor; CCK8, cell counting kit‐8; CDK, cyclin‐dependent kinases; CHOP, CCAAT/enhancer‐binding protein homologous 10 protein; COL, collagen; COX, cyclooxygenase; CTGF, connective tissue growth factor; CXCL3, chemokine ligand 3; CYPs, cytochromes P450; DMSO, dimethyl sulfoxide; DVT, deep vein thrombosis; E 2 , estrogen; ECAR, extracellular acidification rate; EGCG, epigallocatechin gallate; EGFR, epidermal growth factor receptor; eIF2α, eukaryotic initiation factor 2 alpha; ELISA, enzyme‐linked immunosorbent assay; EM, endometriosis; ECSCs, endometriotic cyst stromal cells; EMSA, electrophoretic mobility shift assay; ER, estrogen receptor; ER stress, endoplasmic reticulum stress; ERK, extracellular signal‐regulated kinase; ESR1, estrogen receptor 1; FGFR, fibroblast growth factor receptors; Flk‐1, vascular endothelial growth factor receptor 2; FN, fibronectin; GnRH, gonadotropin‐releasing hormone; GI, gastrointestinal; GSHPx, glutathione peroxidase; GR, glutathione reductase; GRP, G protein‐coupled receptor; GSH, glutathione; H&E, haemotoxylin and eosin; ICC, immunocytochemistry; IF, immunofluorescence; IHC, immunohistochemistry; IFN‐γ, interferon‐γ; IL, interleukin; iNOS, inducible nitric oxide synthase; IRE1, inositol‐requiring enzyme 1; IκB, stimulate inhibitor of NF‐κB; IκK, IκB kinase; JNK, c‐Jun N‐terminal kinase; LATS1, large tumor suppressor kinase 1; LC, lapidated microtubule‐associated proteins 1 A/1B light chain; MAPK, mitogen‐activated protein kinase; MDA, malondialdehyde; MEK, ERK kinase; MIF, macrophage migration inhibitory factor; MIS, Mullerian‐inhibiting substance; MMP, matrix metallopeptidases; mTOR, mammalian target of rapamycin; mRNA, messenger RNA; MTT/MTS, cell proliferation assay; NAC, N‐acetyl cysteine; nESCs, normal endometrial stromal cells; NF‐κB, nuclear factor κB; NK cells, natural killer cells; NO, nitrogen oxide; OCR, oxygen consumption rate; ORAC, oxygen radical absorbance capacity; OSIS, endometriotic stromal cells; PCNA, proliferating cell nuclear antigen; PDGF, platelet‐derived growth factor; PDGFR, platelet‐derived growth factor receptor; PDH, pyruvate dehydrogenase kinase; PERK, endoplasmic reticulum kinase; PGE2, prostaglandin E2; PI3K, phosphoinositide 3‐kinases; PK, pharmacokinetics; PPAR, peroxisome proliferator‐activated receptor; PPD, protopanaxadiol; PR, progesterone receptor; ProEGCG, prodrug of EGCG; PTX, pentoxifylline; RAF, RAF proto‐oncogene serine/threonine‐protein kinase; RT‐qPCR, real‐time reverse‐transcription polymerase chain reaction; Rho, Ras homolog family; ROCK, Rho‐associated coiled‐coil kinase; ROS, reactive oxidative stress; SIRT1, sirtuin 1; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; SQSTM1, sequestosome 1; TCF, T‐cell factor; TCM, traditional Chinese medicine; TGF, transforming growth factors; TNF, tumor necrosis factor; TRAIL, TNF‐related apoptosis inducing ligand; TRAF2, TNF receptor‐associated factor 2; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Wnt, wingless‐type mouse mammary tumor virus integration site family; WST‐1, cell proliferation assay; YAP, Hippo/Yes‐associated protein.\nPk and toxicity profile of drugs can be found on The  Drugs.com  Database,  drugs.com , or on DrugBank Online,  go.drugbank.com , or otherwise as stated.\nA new drug is defined as a chemical that has not been studied in clinical trials for other diseases before EM and a repurposed drug is defined as a chemical that has been studied in clinical trials for other diseases before EM.\nRepresentative clinical indications of drugs shows the original purpose before it was studied on EM. Information was taken from US National Library of Medicine,  ClinicalTrials.gov , or otherwise as stated.\nData were extracted from The  Drugs.com  Database,  drugs.com  or DrugBank Online, go.drugbank.com.\nRepresentative parameters were selected to show efficacy of drugs under corresponding pathophysiology.\nParameters of treated groups with a statistical difference of p < 0.05, compared to controls groups.\nData were extracted from tables or read from graphs.\nDrug accession number is the ID of each drug entry on Drug bank.\nDrug entry on the  drug.com  can be accessed via the URL.\nIncreased levels of E 2  reduce progesterone and inhibit endoplasmic reticulum stress in endometrial cells. \n 157 \n  Increased expression of estrogen receptor (ER) isoforms has been observed in endometriotic lesions, 158 ,  159  suggesting their contribution in regulating proliferation of the lesions. E 2  is mediated by ERα and ERβ as well as by G protein‐coupled receptor 30 (GRP30), which is a seven‐transmembrane receptor. It activates phosphoinositide 3‐kinases (PI3K) and mitogen‐activated protein kinase (MAPK) through the transactivation of the epidermal growth factor receptor (EGFR) in the plasma membrane. 160 ,  161  Chloroindazole and oxabicycloheptene sulfonate are two new chemicals bound to ERα and ERβ, respectively, and both inhibited E 2 ‐driven proliferative and inflammatory activities in a dual action manner in ectopic lesions. This experimental study demonstrated great potential owing to their high potency and efficacy as preventive and therapeutic treatments. In addition, they do not exert any undesirable effects on the reproductive system. Co‐treatment of either ligands with letrozole enhanced the regression of ectopic endometrium, but it did not affect eutopic uterine tissues as with only letrozole. \n 64 \n  Increased COX‐2 and aromatase (P450AROM) levels stimulate E 2  synthesis. 162 ,  163 ,  164  P450AROM inhibitor maintained a low E 2  level and reduced EM lesion size. \n 57 \n  COX‐2‐targeted treatment with celecoxib and indomethacin, which are two available NSAIDs, showed multiple effects on EM. 60 ,  165  The drugs inhibited COX‐2‐mediated prostaglandin E 2  (PGE 2 ), which regulates E 2  formation, \n 53 \n  but caused side effects including reproductive failures and cardiac adverse conditions. \n 166\nEGCG and resveratrol are both natural products that have been studied for EM treatment in clinical trials. They act as anti‐E 2  agents, but with reduced side effects compared with hormonal drugs. 65 ,  69  High doses of resveratrol reduced proliferation by interacting with ERα, and its expression in the endometrium epithelium was reduced to a profound level similar to that achieved with progesterone treatment. Nevertheless, progestogen did not reduce Ki‐67 expression in the endometrium stroma, whereas resveratrol reduced its expression in both the epithelium and stroma. \n 66 \n  EGCG inhibited E 2 ‐stimulated proliferation and VEGF expression in cultured endometriotic glandular cells as well as angiogenesis and lesion growth via VEGF in mouse models. 70 ,  129 ,  167\nNF‐κB is a protein that promotes cell proliferation and inhibits apoptosis in endometrial and endometriotic cells. 168 ,  169 ,  170 ,  171  It is activated by cytokines, including TNF‐α, interleukins (IL)‐1β, and lipopolysaccharide. These stimulate inhibitors of NF‐κB (IκB) to be phosphorylated by IκB kinase (IκK). \n 171 \n  NF‐κB binds to DNA and transcripts the genes of angiogenic and adhesion factors, cytokines, growth factors, and inducible enzymes such as nitric oxide synthase and COX. \n 172 \n  Dienogest is a pregestational steroid of NF‐κB inhibitor, and it inhibits IL‐8 production to attenuate NF‐κB activation in endometriotic stromal cells in vitro. \n 50\nIn EM, MAPK is activated to mediate the intracellular transmission of extracellular signals and induce cellular processes, \n 127 \n  as shown by a high phosphorylated extracellular signal‐regulated kinase (ERK) level. 173 ,  174  RAS binds to RAF and activates ERK kinase (MEK1/2) to phosphorylate ERK, which is a major MARK signaling cascade. \n 127 \n  ERK1/2 regulates c‐fos and c‐jun expression to regulate mitosis and cell viability in endometrial cells under EM. \n 174 \n  E 2 , IL‐1β, and TNF‐α stimulated the phosphorylation of ERK1/2 in endometriotic stromal cells, but not in normal endometrial cells. \n 175 \n  Protease‐activated receptor 2 also activated ERK1/2 in cultured ectopic endometrial stromal cells. \n 176\nSorafenib has completed phase IV clinical trials in several types of carcinoma, and it significantly abrogated the phosphorylation of RAF kinase by 64% via the MAPK/ERK pathway in stromal cells of EM patients. However, weight loss was observed in the xenograft EM mouse models. \n 87 \n  Vemurafenib is FDA‐approved for the treatment of metastatic melanoma and significantly inhibits ERK phosphorylation by over 60% in both endometriotic stromal cells and epithelial cells. \n 89 \n  U0126 is an MEK1/2 inhibitor that increases progesterone receptor (PR)‐αβ levels in endometriotic stromal cells. \n 91 \n  However, although the above treatments were shown to have significant efficacy, treatment of EM with MAPK inhibitors induced adverse effects on reproductive functions in animal models, including ovulation inhibition, embryotoxicity, and teratogenicity. \n 127 \n  Puerarin is a natural product that strongly binds to ERs; its binding affinity to ERs is one‐third that of E 2 , and it suppresses E 2 ‐induced endometriotic stromal cells by 30% via the ERK pathway in vitro, \n 93 \n  and results in reduced adverse effects.\nPI3K phosphorylates phosphatidylinositol 4,5‐bisphosphate (PiP2) into phosphatidylinositol 3,4,5‐trisphosphate (PiP3) and activates protein kinase B (Akt). \n 177 \n  Mammalian target of rapamycin (mTOR), a downstream protein kinase of Akt, is overexpressed in ectopic lesions. 178 ,  179  Reduction of the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) by mutation \n 180 \n  enhanced the phosphorylation of Akt, thus promoting proliferation, inhibiting apoptosis, and reducing PR expression in EM. \n 91 \n  MK2206, an Akt inhibitor, is a drug candidate for cancer treatment that acts by increasing PRβ and PRαβ levels and decreasing the viability of endometriotic stromal cells, without affecting normal cells. \n 91 \n  WIN 55212–2 is a nonselective cannabinoid agonist that binds to cannabinoid receptor (CB)1 or CB2 to inhibit Akt levels and Akt phosphorylation, suggesting the inactivation of the Akt pathway. However, although it reduced the proliferation rate of endometriotic cells, it also reduced that of eutopic endometrial stromal cells. \n 98\nThe Hippo/YAP pathway is important for balancing cell proliferation and apoptosis. Upregulation of this pathway increased the viability of endometriotic cells, whereas knockdown of YAP increased apoptosis and decreased B‐cell/B‐cell lymphoma 2 (Bcl‐2) expressions. \n 181 \n  Verteporfin, a YAP1 inhibitor, inhibited the proliferation of endometriotic stromal cells, production of E 2 , and infiltration of immune cells. \n 75 \n  It is an FDA‐approved drug for the treatment of subfoveal choroidal neovascularization. EM mouse models showed decreased vessel tube formation and cell migration, with no reported effects on reproductive organs, infertility, or transgenerational influence. \n 75 \n  YAP1 is a potential target protein but has not been widely studied in EM.\nThe metabolic pathways toward increased lactate and dysregulation of glycolysis were shown as contributing factors for cancer progression. \n 182 \n  Lactate induces angiogenesis and supplies nutrients to proliferate tumor cells. 182 ,  183  In EM peritoneal mesothelial cells, increased glycolysis, decreased mitochondrial respiration, decreased pyruvate dehydrogenase activity, and increased lactate was also observed. \n 46 \n  Dichloroacetate, a nonhormonal treatment or recurrence prevention of EM, reversed the pathophysiology of EM by inhibiting pyruvate dehydrogenase kinase to activate pyruvate dehydrogenase. \n 46 \n  Although dichloroacetate has completed a phase III clinical trial for lactic acidosis in 1998 and has widely studied in cancer, it has not been approved by the FDA for therapeutic use in cancer.\nApoptosis is a programmed cell death process that maintains the balance between the growth and differentiation of cells for tissue renewal. It is regulated by selective chromatin internucleosomal cleavage to shrink the cells. \n 184 \n  Apoptosis is important in the normal endometrium to remove dysfunctional cells and repair tissues during the menstrual cycle. \n 185 \n  Apoptotic cells were found to be more predominant in the endometrial epithelium glands than in the stroma. \n 186 \n  Cell apoptotic activity was found to be relatively low in EM. \n 187 \n  This can be explained by the reduced expression of proapoptotic factors (e.g., Bcl‐2‐associated X [Bax] and Bcl‐2 associated agonist of cell death [Bad]), overexpression of antiapoptotic factors (e.g., Bcl‐2), and dysregulation of cell cycle. 188 ,  189  Endometriotic cells could not express surface receptors to trigger proapoptotic proteins; neither apoptotic signals were appropriately transduced, leading to proliferation being triggered instead. \n 188 \n  GnRH agonists, such as leuprolide acetate or the preclinical nonhormonal drug propofol, increased the levels of proapoptotic proteins, as well as decreased the levels of antiapoptotic proteins and promitogenic cytokines. 52 ,  100  Melatonin is highly effective in amplification of apoptotic activity via regulating MMP‐3 signal, was able to regress EM at either early or late stage. Melatonin in high dose and long‐term treatment shows no adverse effects in EM rodents. \n 63\nThe signaling pathways MAPK/ERK, PI3K/Akt, and NF‐κB also regulated apoptosis in endometriotic cells. ERK1/2 was activated as an antiapoptotic protein in eutopic and ectopic endometrial glands throughout the menstrual cycle. \n 174 \n  Non‐E 2  targeted treatments, such as selective PGE 2  inhibitors, inhibited PGE 2  receptor (EP) 2 and EP4 to induce apoptosis via multiple pathways including ERK1/2, AKT, and NF‐κB. They enhanced apoptosis by approximately 50% in both epithelial and stromal cells; thus, owing to their efficiency as selective or combination inhibitors, they are ideally used to treat stage I and II EM. \n 95 \n  PGE 2  inhibitors are preferred to COX‐2 inhibitors due to their fewer adverse effects and lack of hypoestrogenic effects. \n 95\nBAY11‐7085 is an NF‐κB inhibitor that inhibits cell viability and enhances apoptosis in endometriotic cells by seven fold but induced less profound results in normal endometrial cells. \n 62 \n  The activity of Bay11‐7085 has been shown in in vitro studies, but there has been no clinical study of its therapeutic potential. Ginsenoside Rg3, genistein, and curcumin are found in natural products, and they enhanced apoptosis via regulation of the NF‐κB pathway. 79 ,  85  In addition, ginsenoside Rg3 neutralized the effect of TNF‐α to regulate proliferation. \n 79 \n  Genistein had a similar capability as a GnRH agonist, that is, inhibiting transforming growth factor (TGF)‐β to regulate NF‐κB. Expression of Bcl‐2 was suppressed, whereas that of Bax was enriched. It also reduced COX‐2 and PGE 2  expression to levels comparable to those in the control group. \n 85 \n  Curcumin inhibited MMP‐3 and increased the Bax/Bcl‐2 ratio by upregulating tumor protein p53 (p53). \n 81 \n  These natural products are highly attractive owing to their potential efficacies and minimal side effects reported in in vitro and in vivo studies of EM and clinical studies of other diseases.\nAkt is a pleiotropic regulator of apoptosis that increases endometriotic cell survival and decreases apoptosis. \n 190 \n  Akt/mTOR can be inhibited by endoplasmic reticulum stress. \n 51 \n  Tunicamycin enhanced TNF‐related apoptosis‐inducing ligand‐induced apoptosis by inducing endoplasmic reticulum stress in endometriotic stromal cells. The effect was more potent in endometriotic cells than in eutopic endometrial cells \n 73 \n ; however, its action mechanism and pharmacokinetics profile have yet to be elucidated.\nTranscription of antiapoptotic Bcl‐2 protein was increased by E 2  through the promotion of thymic stromal lymphopoietin. \n 191 \n  Extranuclear kinases are activated by an elevated ER complex to trigger a rapid nongenomic signaling cascade and inhibit apoptosis in stromal and epithelial cells. 192 ,  193  Genistein interfered with the E 2 /ER pathway to induce apoptosis and apoptotic proteins in endometrial hyperplasia. \n 194 \n  Moreover, the activity of E 2  strongly regulates TNF‐α‐induced effects. In a healthy endometrium, TNF‐α stimulated apoptosis. In eutopic and ectopic endometriotic cells, TNF‐α stimulated proliferation and inhibited apoptosis instead. \n 195 \n  In endometriotic lesions, apoptosis signal‐regulating kinase (ASK‐1), a TNF‐α induced apoptosis complex I, interacted with ERβ as well as serine/threonine kinase receptor‐associated protein (STRAP) and 14‐3‐3 proteins. \n 62 \n  Formation of this complex disrupted the association of TNF‐receptor‐associated factor 2 (TRAF2) and ASK‐1 for TNF‐α‐induced apoptosis. 196 ,  197  TNF‐α‐induced apoptosis complex I, complex II, and apoptosome were all inhibited, which dysregulated apoptosis and activated the invasiveness of lesions for survival. In addition, in endometriotic tissue, TNF‐α from macrophages and natural killer (NK) cells induced the generation of the steroid receptor coactivator (SRC)‐1 isoform from cleaved MMP‐9. \n 198 \n  ERβ interacted with the caspase (CASP)‐8 and SRC‐1 isoforms to prevent activation of TNF‐α‐induced apoptosis complex II in endometriotic lesions in ectopic sites. \n 62 \n  Therefore, inhibition of ASK1/ERβ/STRAP‐14‐3‐3 and ERβ/CASP8/SRC‐1 protein complex are potential therapeutic targets to regulate apoptosis via the E 2 /ER/TNF‐α pathway.\nAutophagy is a process related to nonapoptotic cell death and is defined as self‐degradation. It balances the energy sources by removing misfolded proteins, damaging organelles, and eliminating intracellular pathogens. It promotes the proteolytic degradation of cytosolic components at the lysosome. \n 199 \n  Recently, there have been more studies on the role of autophagy in both accelerating and decelerating the pathogenesis of EM. To examine the pathophysiology of autophagy in regulating EM, we divided the section into antiautophagy and proautophagy to discuss the controversies in the progression of EM.\nDownregulation of apoptosis favors the stimulation of autophagy, thus promotes EM growth. \n 200 \n  A significant reduction in apoptosis inducer p53 mediated by Akt, an increased lapidated microtubule‐associated protein 1A/1B light chain 3 (LC3)‐II, and a significant decrease in sequestosome 1 (SQSTM1) were observed in ovarian endometrioma. \n 200 \n  LC3‐II is a standard autophagy marker while SQSTM1 is an autophagy adaptor protein that transfers ubiquitinated proteins to the autophagic machinery and is degraded via autophagy to indicate the activation of autophagic flux. 197 ,  198 ,  199 ,  200 ,  201  Hypoxia upregulated autophagy in endometriotic cells to induce HIF‐1α. \n 202 \n  Overexpression of HIF‐1α under normoxic conditions also induced autophagy. \n 203 \n  Decreased expression of homeobox A10 (HOXA10) induced autophagy in EM, which was attributed to excessive inflammation. \n 204 \n  It contributed to mitochondrial damage, increased PGE 2 , and increased mitochondrial ROS, 203 ,  204  all stimulated autophagic processes. An increased oxidant heme oxygenase (HO)‐1 was observed in ovarian endometrioma to activate an adaptive defense mechanism and negatively modulate inflammation and apoptosis, and positively stimulated autophagy. \n 200 \n  A combination therapy with MK2206 and chloroquine was found to be more effective than with either MK2206 or chloroquine in reducing endometriotic cell viability and preventing regrowth by inhibiting autophagy. \n 102 \n  SQSTM1 expression was significantly upregulated. \n 102\nUpregulation of autophagy promoted apoptosis and suppressed cell growth and invasion in EM. 205 ,  206  Endometriotic stromal cells have an abnormal response to progesterone, which suppresses PTEN expression, suppresses autophagy, and reduces apoptosis in the menstrual cycle via the AKT/mTOR pathway. \n 207 \n  Increased expression of YAP significantly decreased autophagy through the mTOR pathway in eutopic endometrium stromal cells. \n 208 \n  Mullerian‐inhibiting substance (MIS) induced autophagy and apoptotic cell death and inhibited proliferation in vitro. \n 104 \n  MIS, also known as anti‐Müllerian hormone, however, was found to be increased in EM lesions and in the serum of women with ovarian endometrioma and promoted inflammation. More preclinical data are required before the clinical application of this agent in EM treatment. 209 ,  210  A ginsenoside metabolite, protopanaxadiol (PPD), reduced ERα expression and induced PRα expression in vitro and in vivo, which then induced autophagy and suppressed lesion growth, resulting in a significantly different expression of autophagy‐related genes, including downregulated estrogen receptor (ESR1), SQSTM1, and TGF‐β levels as well as upregulated CASP‐3, ATG ‐3/‐5/‐12 after treatment. \n 103\nCell migration and invasion are critical processes for EM establishment according to the implantation theory. EM is believed to occur due to the shedding of endometrial cells and then migration to ectopic sites. 15 ,  211  Migration of endothelial cells mediates angiogenesis and plays a role in the pathophysiology of EM. \n 212\nThe wingless‐type mouse mammary tumor virus integration site family (Wnt) plays a role in developmental processes and homeostasis. β‐catenin is crucial in regulating the cell cycle, which includes proliferation, differentiation, and migration in ectopic lesions. \n 213 \n  In the presence of Wnt ligands, an accumulation of β‐catenin translocates to the nucleus and interacts with T‐cell factor/lymphoid enhancer‐binding factor (Tcf/LEF) transcription factors to activate the Wnt/β‐catenin signaling pathway. \n 107 \n  Wnt/β‐catenin was found to be abnormally activated in EM. \n 214 \n  Multi‐drug resistance protein 4 (MRP4) regulates Wnt/β‐catenin signaling by stabilizing β‐catenin activity. It was involved in the pathogenic transformation of EM endometrium, confirmed in the ectopic lesion. In MRP4‐knockdown endometrial epithelial cells, reduced activity of β‐catenin was found to downregulate Wnt/β‐catenin signaling. \n 215\nOverexpression of T‐cadherin inhibited the invasion and migration of cells in EM, and the phosphorylation of heat shock protein (HSP)‐ 27 and c‐Jun N‐terminal kinase (JNK)‐1/2/3 was promoted. MMP‐2/‐9 and vimentin expression was lowered in endometriotic cells. \n 216 \n  MMP‐2/‐9 and Cyclin D1 are targets of Tcf/β‐catenin genes and were found to be upregulated in endometrial epithelial or stromal cells of EM, \n 107 \n  MMPs are responsible for regulating migration, invasion, and angiogenesis by balancing growth factors and cytokines, and high expression of MMPs in EM favors lesions. \n 217 \n  PKF115‐584 and CGP049090 are fungal derivatives and were screened through high‐throughput assay to disrupt Tcf/β‐catenin complex, \n 218 \n  significantly inhibiting MMP‐9 activity and cell invasiveness in epithelial and stromal cells to a level close to that of normal endometrium. \n 108 \n  However, they have not been widely studied in EM. Genistein regulates invasion and migration through downregulation of MMP‐2/‐9 by targeting NF‐ κ B, as shown in an in silico study and in an EM mouse model. \n 112 \n  In addition, Wnt/β‐catenin is important for stem cell maintenance and tissue homeostasis \n 107 \n ; thus, an antagonist of Wnt/β‐catenin may have potential side effects. Moreover, Wnt2 is secreted by ectopic stromal cells, which induces β‐catenin signaling activity in ectopic endometrial epithelial cells, as well as expressions of the growth‐associated proteins in endometrial epithelial cells. \n 48 \n  Wnt2/β‐catenin is a pathway involved in the communication of stromal and epithelial cells in EM, which can be modified by metformin. \n 48\nRas homolog family member A/Rho‐associated coiled‐coil kinase (RhoA/ROCK) plays a major role in cell migration via phosphorylation of cytoskeletal regulatory proteins and results in actin depolymerization, actomyosin contraction, endothelial cell adhesion, and migration. \n 219 \n  ROCK in the endothelial cytoskeleton is activated by proangiogenic stimuli. \n 219 \n  VEGF stimulates RhoA/ROCK and mediates endothelial cell migration. \n 220 \n  ROCKII regulates cell body contraction during migration. \n 221 \n  It is a positive regulator of p27 to further activate cell migration in endometrial stromal cells and regulate RhoA in the cells. \n 222 \n  Fasudil is a ROCK inhibitor used clinically and has the potential for treating EM by reducing endometriotic cell viability and inducing apoptosis by targeting Rho/ROCK. \n 115\nRecently, EM was defined as a profibrotic condition, as a new concept by Vigano et. al. 223 ,  224  The crucial role of fibrosis and differentiation of myofibroblasts in the progression of EM lesions have been reported. Fibrosis is the pathological activity when activated myofibroblasts accumulate leading to contraction of the collagenous extracellular matrix and anatomical structure disruption. The event of fibrosis justifies EM‐associated morbidity and adhesiveness and is considered a potential EM therapeutic target. 223 ,  224\nTGF‐β1 is a stimulating factor that triggers the production of collagen and transition of epithelial to mesenchymal phenotype, leading to fibrosis. TGF‐β1 was found to be significantly increased in the peritoneal fluid of women with EM. \n 225 \n  Wnt signaling is required for TGF‐β1‐mediated fibrosis. \n 226 \n  Matsuzaki and Darcha \n 110 \n  also showed that the Wnt/β‐catenin pathway was involved in fibrogenesis in EM. PKF1150‐584, CGP049090, and EGCG significantly inhibited TGF‐β1‐induced fibrotic markers, including α‐smooth muscle actin (α‐SMA), type I collagen, fibronectin, and connective tissue growth factor in stromal cells via Wnt/β‐catenin signaling, with EGCG showing the greatest effects. 110 ,  111  ICG‐001 and C‐82 are CBP inhibitors. They are also metabolites of PRI‐724, which is under clinical trials for its antitumor activity, \n 227 \n  they inhibited fibrosis via Wnt/β‐Catenin signaling, with ICG‐001 showing great efficacy in upregulating apoptosis and inhibiting migration as well as C‐82 showing potent inhibition of proliferation and cell viability. \n 106\nActivation of the Rho/ROCK signaling pathway was associated with fibrosis in EM. \n 228 \n  Heparin has completed phase IV clinical trials for several medical indications, including anticoagulation and cancer. It inhibited RhoA, ROCKI, ROCKII, and α‐SMA expression and activated the Rho/ROCK pathway to attenuate endometriotic stromal cell contractility, differentiation, and fibrosis. \n 117\nAngiogenesis is highly regulated in the female reproductive system, and it is a process that results in the formation of new blood vessels from existing ones. Three mechanisms of angiogenesis have been described as sprouting, elongation, and intussusception. \n 229 \n  It provides neovascularization to deliver essential nutrients and oxygen supply for the growth of endometriotic lesions. \n 230\nVEGF regulates angiogenic, endothelial cell‐specific mitogenic, and vascular permeability activities of endometrial and endometriotic cells through vascular endothelial growth factor receptor (VEGFR) 1–3 on the microvascular endothelial cell surface. The VEGF family helps in establishing and maintaining endometriotic foci. 231 ,  232 ,  233  VEGFR2 is a highly active kinase that plays a major role in angiogenesis. VEGF binds to two proximal VEGFR2 receptors, promotes vascular permeability, increases the migration and proliferation of endothelial cells, and contributes to the formation of new blood vessels. 234 ,  235  Sunitinib, SU6668, SU5416, sorafenib, and pazopanib were originally indicated as anticancer drugs but were further repurposed and tested for efficacy against EM. 119 ,  120 ,  123 ,  126 ,  128  SU5416 selectively bound to VEGFR, and only reduced graft size by 5%. 123 ,  126 ,  236  SU6668, a multi‐kinase inhibitor, reduced the endometrial graft by 25% by blocking VEFFR‐2, fibroblast growth factor receptors (FGFR)‐1, and platelet‐derived growth factor receptors (PDGFR)‐β. 123 ,  236  Sunitinib regulates angiogenesis and apoptosis through multi‐kinase inhibition, regressing 50% cyst in an EM rat model. \n 120 \n  The effects of pazopanib, sunitinib, and sorafenib on VEGF/VEGFR protein kinase pathways and their actions in EM were compared by Yildiz et. al., \n 128 \n  which showed that pazopanib had better efficacy than the control and other treatments, reducing EM lesions by at least 45%, but Sorafenib was better in regulating VEGF. \n 128 \n  However, tyrosine kinase inhibitors that regulate VEGFR are associated with a significant risk of treatment toxicities. \n 237 \n  In sarcoma, pazopanib treatment led to a higher incidence of adverse effects, including fatigue and hypertension, compared with sunitinib or sorafenib. \n 237 \n  An alternative VEGF regulator, EGCG, significantly inhibited lesion growth by suppressing VEGFC/VEGFR2 signaling. Overexpression of VEGFC induces migration of endothelial cells, increases vascular permeability, and induces angiogenesis and endometriotic lesions growth. 70 ,  129  Prodrug of EGCG (ProEGCG), reduced lesion size, weight, and VEGF concentrations in plasma to a greater extent than the parent EGCG molecule. More importantly, there were no signs of side effects on reproductive tissues. \n 130 \n  Quinagolide, a dopamine receptor 2 agonist, is under phase II clinical trial to examine its efficacy in reducing EM lesion size and related pain. It can completely reverse the size of lesions by downregulating the VEGF/VEGFR2 pathway in EM. \n 135 \n  It has an acceptable safety profile and does not stimulate serotonin receptor subtype 2b to proliferate fibroblasts in cardiac valve tissues, and thus holds great potential as an alternative of tyrosine kinase inhibitor for EM. \n 135\nUnder normoxic conditions, HIF‐1α is regulated via proteasome‐mediated degradation. \n 238 \n  However, under hypoxic conditions, HIF‐1α escapes ubiquitination and binds to hypoxia‐responsive enhancer on VEGF genes to upregulate their expression. \n 239 \n  HIF‐1α was upregulated in lesions, thus promoting VEGF expression in an EM mouse model. \n 240 \n  Increased VEGF secretion was observed in hypoxia‐induced endometrial stromal and glandular cells compared with that under normoxic conditions. \n 241 \n  Oxidative stress also increased VEGF secretion, as shown by the results obtained after incubating endometrial epithelial cells with oxidized low‐density lipoprotein. \n 242 \n  In the EM peritoneal environment, PGE 2  was upregulated to elicit cell signals through upregulation of VEGF and FGFR. It induced the expression of COX‐2 and synthesis of E 2  in ectopic endometrial cells to increase the production of MMP, thus enhancing VEGF expression and inducing angiogenesis. 229 ,  243  TNF‐α mediates the angiogenic activity of macrophages, which stimulates endothelial cell migration and induces the release of VEGF and the formation of bloodvessel. \n 244 \n  Pyrrolidine dithiocarbamate inhibited NF‐κB activation and attenuated TNF‐α‐mediated VEGF and MMP‐9 expressions. \n 132 \n  Pentoxifylline attenuated TNF‐α mediated effects in other diseases, requires further investigation of this in EM, but it suppressed angiogenesis by reducing VEGFC and VEGFR2 (Flk‐1) expression levels in glandular cells of endometriotic lesions. \n 133 \n  Pentoxifylline is an immunomodulatory agent and has completed a phase III clinical trial of EM‐associated infertility. The clinical trial did not present any data on lesion progression or recurrence, only on pregnancy rate. \n 245\nThe Rho/ROCK pathway regulates VEGF‐mediated endothelial cell activation and vessel stability. 233 ,  246  RhoB mitigates VEGF‐induced vessel sprouting via the RhoA/ROCK signaling pathway. \n 247 \n  RhoA/ROCK activity can be blocked by inhibiting protein prenylation in endothelial cells to reduce migration and adhesion. \n 248 \n  Avian myelocytomatosis virus oncogene cellular homolog (C‐Myc) is a target of the PI3K/Rho/ROCK signaling pathway and regulates VEGF expression. Under hypoxic conditions in EM, guanosine triphosphate (GTP)‐bound Rho was regulated in a PI3K‐dependent manner to induce VEGF by binding to C‐Myc without suppressing the induction of HIF‐1α. \n 249 \n  ROCK activation initiates E 2 ‐induced angiogenesis. \n 219 \n  Inhibitors that target the Rho/ROCK pathway should be further investigated for their ability to regulate angiogenesis, migration, invasion, and fibrosis of endometriotic cells.\nOxidative stress is the imbalance between ROS production and antioxidant function, which plays a main role in EM progression. \n 250 \n  ROS are molecules that have unpaired electrons and can damage lipids, nucleic acids, and proteins. 251 ,  252  Apoptotic endometrial tissues and macrophages induced oxidative stress in EM through retrograde menstruation. \n 253 \n  Oxidative stress causes DNA hypermethylation and histone modification, which are linked to aberrant endometrium development in EM. \n 254\nThe production of ROS in the progression EM could be achieved through several pathways, including activation of inflammatory cytokines, MMPs, and transcriptional factors, such as NF‐κB. \n 255 \n  Environmental factors, such as reproductive toxins, can also increase oxidative stress and decrease the expression of antioxidant enzymes. \n 256 \n  Di‐2‐ethylexyl phthalate is used as a plasticizer and solvent in cosmetic and consumer products, and they altered the NF‐κB signaling pathway and expression levels of ER and PR in human endometrial stromal cells via activation of the MAPK/ERK and PI3K/Akt signaling pathways. \n 257\nBalancing ROS production and antioxidant function by inhibiting free radicals or increasing antioxidant levels is important to regulate oxidative stress. Antioxidants include the enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), HO, and catalase, as well as nonenzymatic molecules such as vitamins A, C, and E. 250 ,  252 ,  255  Significantly lower levels of antioxidants were found in the peritoneal fluid of EM, which indicated that women with EM had a low free radical‐scavenging ability. 255 ,  258 ,  259  N‐Acetyl cysteine (NAC) is an antioxidant that inhibits ROS as well as abrogates ERK activation and proliferation. \n 137 \n  EGCG and resveratrol are both well‐known natural antioxidant supplements for the treatment of EM and other diseases, including cancer. 130 ,  138 ,  260  Resveratrol acts as a radical scavenger, and it significantly regressed endometriotic implants, decreased lipid peroxidation, and increased at least 50% endogenous antioxidant capacity in tissues and serum in EM. \n 138 \n  The antioxidant effects of ProEGCG against EM were significantly greater than those of EGCG and at least four fold that of the control. \n 130 \n  Melatonin reduced the level of oxidative stress markers and increased level of antioxidants in EM. EM implants in rat were significantly regressed. 142 ,  143  Caffeic acid found in plants exerted similar antioxidant effects in EM and an enhanced nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2) regulated antioxidant enzymes in EM. 141 ,  261\nNO is a vasodilator that mediates endothelium‐dependent vasodilation and angiogenesis. \n 262 \n  NO has an unpaired electron and is a highly reactive free radical. The formation of NO requires NO synthase (NOS),  l ‐arginine, oxygen, and a number of cofactors, including nicotinamide adenine dinucleotide phosphate, flavin mononucleotide (FMN), and flavin adenine dinucleotide. \n 263 \n  Macrophages increased IL‐10 in EM and stimulated NO \n 264 \n ; NO and NOS levels were increased in endometrial tissues in EM. \n 265 \n  Increased E 2  level activated the formation of NO, \n 266 \n  implying that macrophages and E 2  regulate NO‐mediated oxidative stress in EM.\nIron carries hemoglobin throughout the body, an overproduction of it not only enhances epithelial cell proliferation but also induces oxidative stress. 267 ,  268  Ferritin is a cellular iron storage that generates hydroxyl radical via Fenton reaction to initiate a free radical chain reaction, namely lipid peroxidation. 37 ,  269  McKinnon et al. \n 37 \n  reviewed studies on the implication of mTOR on iron homeostasis and suggested the dysregulation of mTOR in EM could overload iron levels to stimulate oxidative stress. Currently, there is lack of pharmaceuticals targeting iron‐mediated oxidative stress in EM and regulating the mTOR signaling pathway might reduce oxidative stress.\nImmune system dysregulation and chronic inflammatory response are characterized in EM. 270 ,  271  The adaptive immune system with increased quantity of regulatory T (Treg) cells and a shift towards type 2 immune response fail to recognize the endometriotic cells in the peritoneal cavity. \n 272 \n  On the contrary, the innate immune system in EM is characterized by an enhanced activation state of macrophages, along with upregulated cytokines, but downregulated phagocytosis, \n 273 \n  as well as a reduced cytotoxicity of natural killer (NK) cells, \n 274 \n  and an altered population of dendritic cells. \n 275 \n  These promote inflammation and contribute to the implantation process in EM and new drugs that modulate these specialized cells hold promise as a novel immunotherapy for EM.\nMacrophages exert their inflammatory effects against tumors via host defense mechanisms. \n 276 \n  IL‐1 is a proinflammatory cytokine secreted by activated monocytes, macrophages, or NK cells, and is responsible for activating lymphocytes to reduce immune surveillance and stimulate PGE 2  via COX‐2 in EM stromal cells. 271 ,  277 ,  278  IL‐6 is responsible for stimulating B‐cell activity and T‐cell differentiation. The levels of IL6 in serum and peritoneal fluid are high, but its receptor is reduced in EM. However, endometriotic cells are resistant to its growth‐inhibitory effects. 271 ,  279 ,  280  VEGF and TNF‐α are proinflammatory cytokines secreted by activated lymphocytes, neutrophils, NK cells, and macrophages to initiate the inflammatory cascade. \n 271\nNiclosamide is an FDA‐approved nonsteroidal therapy for antihelminth \n 281 \n  and was found to inhibit the proliferation and growth of endometriotic lesions. It reduced MAPK, WNT, and inflammation signaling‐related genes, such as NF‐κB and signal transducer and activator of transcription 3, in an EM mouse model. No disruption to reproductive function was observed, indicating potential therapeutic efficacy and safety for EM treatment. \n 154 \n  NAC regressed lesions by suppressing COX‐2 and MMP‐9 expression. Its side effect is mild and seemed to not interfere with fertility in vivo. \n 144 \n  Crocin, curcumin, and metformin inhibit proinflammatory cytokines and chemokines, including TNF‐α, IL‐1β, IL‐6, VEGF, and so forth. 148 ,  149 ,  155  These are responsible for recruiting and activating macrophages, neutrophils, and NK cells to the EM site and further enhancing angiogenesis and inflammation. 155 ,  282  Acai, a natural product found in plants from the Amazon region, has completed phase III clinical trials as an antioxidant agent. It reduces EM lesions by targeting active macrophages, VEGF, and COX‐2. \n 156 \n  Resveratrol inhibited inflammatory responses by reducing peritoneal and serum cytokines, \n 150 \n  as well as activating sirtuin 1 (SIRT1) to significantly suppress IL‐8 in TNF‐α‐induced endometriotic stromal cells via NF‐κB. \n 151 \n  SIRT1 has a dual function as a tumor suppressor or promoter, \n 283 \n  and it is a potential target protein, considering that it is a strong regulator of the inflammatory responses, apoptosis, and oxidative stress in EM. \n 284 \n  Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is upregulated in peritoneal fluid in women with EM. It activates the MAPK/ERK pathway, stimulates COX‐2, and produces PGE 2  in ectopic endometrial cells. MIF also contributes to angiogenesis via its effect on endothelial cell proliferation. \n 285 \n  ISO‐1 is a MIF antagonist and a leading molecule discovered to treat sepsis. \n 286 \n  It inhibited angiogenic and proinflammatory pathways via VEGF/VEGFR in peritoneal EM in vivo, without interrupting the reproductive cycle. \n 287\nIn EM, increased ESR2/E 2  induces COX‐2 and PGE 2 , upregulates macrophages and NF‐κB, 288 ,  289  and leads to oxidative stress. \n 255 \n  ERβ modulates macrophage infiltration via NF‐κB in EM \n 290 \n  and induces IL‐1β by interacting with the inflammasome complex to evade immune surveillance and promote the attachment of lesions at the endometriotic sites. \n 196 \n  E 2  activates thymic stromal lymphopoietin and induces the secretion of endometrial stromal cells‐associated growth‐promoting cytokines, including monocyte chemoattractant protein 1 and IL‐8, via the JNK and NF‐κB pathways. \n 291 \n  IL‐6 reduces E 2  production in human granulosa tumor cells via the MAPK signaling pathway, \n 292 \n  implying its possible targeting of E 2  biosynthesis in EM. Puerarin reduced the level of ERβ, but not ERα, by inhibiting P450AROM. In a rat model, simultaneous reduction of E 2,  COX‐2, and PGE 2  expression levels, as well as enhancement of the metabolism of E 2  into estrone, \n 152 \n  led to the inhibition of lesion growth in the ectopic endometrium tissues. In another study, ginsenoside PPD inhibited the E 2  signal, thus activating the cytotoxicity of NK cells against ectopic endometrial stromal cells to regulate cell death. This was also confirmed in peritoneal fluids of the EM mouse model. \n 103\n\nIn the treatment of EM, targeting a specific pathway, or multiple pathways alleviate the lesions. Targeting a single molecule can lead to several anti‐EM effects, as downstream transduction elements are usually connected to a series of molecular events as secondary responses. However, owing to synergistic effects, a multiple target therapy may have a greater suppressive effect on lesions compared with a single targeted therapy. \n 196 \n  Table  4  summarizes several single pharmaceuticals with multiple molecular targets, which affect multiple signaling pathways in a complex disease such as EM.\nPharmaceuticals that hold multiple molecular targets to different pathophysiology for endometriosis treatment\nAbbreviations: AKT, protein kinase B; AMPK, adenosine monophosphate‐activated protein kinase; CASP, caspases; CHOP, CCAAT/enhancer‐binding protein homologous 10 protein; COX, cyclooxygenase; DPPH, 2,2‐diphenyl‐1‐picrylhydrazyl; E 2 , Estrogen; EGCG, epigallocatechin gallate; ER, estrogen receptor; ERK, extracellular signal‐regulated kinase; ESR1, estrogen receptor 1; HMGB1, high mobility group box 1; H 2 O 2 , hydrogen peroxide; IKKB, IκB kinase beta; MAPK, mitogen‐activated protein kinase; MMP, matrix metallopeptidases; NAC, N‐acetyl cysteine; NF‐κB, nuclear factor κB; NK cells, natural killer cells; NOD2, nucleotide‐binding oligomerization domain‐containing protein 2; Nrf2, nuclear factor erythroid 2–related factor 2; O 2 , oxygen; OH, hydroxide; P450AROM, aromatase; PI3K, phosphoinositide 3‐kinases; PR, progesterone receptor; REDD1, protein regulated in development and DNA damage response 1; ROS, reactive oxidative stress; SIRT1, sirtuin 1; TCM, traditional Chinese medicine; TGF, transforming growth factors; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Wnt, wingless‐type mouse mammary tumor virus integration site family.\nMelatonin is a natural substance produced by plants. It is also a hormone produced in the pineal gland to regulate neuroendocrine functions and inhibits LH and FSH secretion from the anterior pituitary gland. \n 293 \n  Melatonin acts as an antioxidant and anti‐inflammatory agent and is currently under phase 2 clinical trial for reducing EM‐related pain. Another randomized, double‐blind, and placebo‐controlled clinical trial of melatonin was completed in 2013. The results of the study showed that melatonin acts as an analgesic and can relieve EM‐related chronic pain. \n 294 \n  Melatonin receptor (MR)1A and MR1B are significantly upregulated in peritoneal EM lesions compared with those in the eutopic tissue. Melatonin has been shown to reduce EM lesions in various studies. It inhibits cell proliferation and modulates endometrial epithelial cell function. \n 295 \n  Melatonin also inhibits angiogenesis via VEGF and oxidative stress via regulating radical scavenging activity and amplifies apoptotic activity via CASP3 mediated pathway in vivo and  in vitro  in EM. 63 ,  142 ,  143  Melatonin has no adverse effects on reproductive functions, instead, it can improve ovarian functions, and thus has potential to treat EM‐related infertility. 296 ,  297  High‐dose intravenous treatment of pain and sepsis with melatonin showed no adverse effects. \n 298 \n  Its bioavailability is 15%. \n 299 \n  Long‐term therapeutic investigation of melatonin in EM should be conducted to elucidate its ability to regulate E 2  functions in EM.\nMetformin was shown to target multiple pathways \n 300 \n  by regulating stromal‐epithelial cell communication in EM via Wnt2‐mediated signaling \n 48 \n  and exerted an anti‐inflammatory effect through regulating cytokines. \n 149 \n  Although a mild side effect was implied, \n 149 \n  metformin regulated reproductive functions, \n 301 \n  and improved conception in EM patients by inhibiting serum cytokine production. \n 149 \n  Metformin is available in the market as a treatment for type 2 diabetes and PCOS in women. Considering its low cost, metformin was advocated to be used as a long‐term treatment. \n 302 \n  NAC, an acetylated form of cysteine, has been prescribed as an antidote since the 1960s. It replenishes intracellular glutathione levels and modulates the redox environment; therefore, NAC is a strong antioxidant. \n 303 \n  In EM, it acts as an antioxidant, antiproliferative, anti‐inflammatory, and anti‐invasiveness agent via ROS‐scavenging mechanism or through regulating cytokines in vitro and in vivo. 137 ,  144  NAC is highly efficacious at low doses, and with no adverse effects in EM. \n 144 \n  Long‐term adverse effects are also limited, including no effect on fertility. 137 ,  144  NAC is considered to have a good safety profile and has been evaluated in phase 4 clinical trials for treating gastrointestinal and metabolic diseases. 303 ,  304  Its pharmacokinetics and toxicity profiles are available; its terminal half‐life is 6.25 h after oral administration and bioavailability is 9.1%. \n 305 \n  NAC is commercially available and cost‐effective as a dietary supplement in the market; however, studies on its efficiency in EM are limited, requiring more preclinical evidence.\nNatural products have a long history of use in the management of medical conditions. Research advances in analytical and synthetic chemistry have improved the identification and isolation of active compounds from natural products. EGCG is a polyphenol catechin from green tea and a well‐known antioxidant. It exerts efficacy against diseases including cancer, diabetes, and inflammation. \n 306 \n  In EM, it exerts ant antiangiogenetic effect via the VEGFC/VEGFR2 pathways, 70 ,  129  antioxidant effects via ROS‐scavenging mechanism, \n 130 \n  antiproliferative effect via reduction of E 2  production, and anti‐migration and anti‐invasion effects via TGF‐β1‐induced phosphorylation of ERK1/2 and MAPK pathways, \n 167 \n  thus inhibiting the development and growth of lesions. Promising evidence of its high potency and efficacy, and without major side effects in reproductive functions were reported. 130 ,  167  EGCG is currently under phase 2 clinical trial for reducing lesion size and pain as well as an evaluation of its safety profile in EM. On the contrary, EGCG act as an adjuvant that brings synergistic effects, as well as reduces adverse effects in cancer treatment. \n 307 \n  This suggests a potential role of EGCG in combination therapy with current EM treatment. However, the low bioavailability of EGCG has limited its attractiveness in the market. \n 308 \n  ProEGCG, is a prodrug of EGCG, shows higher bioavailability and greater efficiency than EGCG to reduce lesions in vivo. \n 130 \n  More studies should be conducted to confirm the underlying mechanism of ProEGCG in the treatment of EM. Resveratrol is a polyphenol found in grapes. In EM, it reduces proliferation via an anti‐E 2  mechanism targeting ESR1, \n 66 \n  inhibits inflammatory responses via radical scavenging, \n 138 \n  and inhibits angiogenesis by reducing the cytokines COX‐2 and VEGF \n 150 \n  and activating SIRT1. \n 151 \n  Resveratrol has completed a phase 4 clinical trial in EM and is safe and effective in relieving EM‐related pain, as well as in reducing serum CA125 and prolactin levels. Resveratrol is well‐known for its chemopreventive property. It also has a promising clinical profile in cancer treatment, nevertheless, the rapid metabolism rate of resveratrol has limited its efficacy in vivo. \n 309\nCurcumin, genistein, ginsenoside, and puerarin are not under any EM clinical studies but have been clinically evaluated in breast cancers, endometrial carcinoma, endothelial functions, and so forth. They have been studied for their action mechanism against EM in primary cells, cell lines, and animal models. Curcumin, which is found in ginger and turmeric, enhances apoptosis by increasing the Bax/Bcl2 ratio through targeting of MMP‐3 via NF‐κB \n 81 \n  and regulates angiogenesis and inflammation by targeting chemokines and cytokines \n 155 \n  in EM. It has multiple biological effects in different diseases, including cancer and inflammatory diseases. It establishes a good safety profile with no acute toxicity. \n 310 \n  Genistein is an isoflavone that acts as an E 2  agonist or antagonist to manage postmenopausal symptoms. In EM animal models, genistein downregulated MMP‐2/‐9 and regulated cell invasion and migration by targeting NF‐κB. \n 311 \n  It also regulated NF‐κB by inhibiting TGF‐β. \n 85 \n  Long‐term treatment with genistein lower the incidence of endometrial hyperplasia and provided support for bone formation in postmenopausal women. 83 ,  312  It acts as a chemopreventive and chemotherapeutic agent against cancers and has synergistic effects with other anticancer drugs. \n 313 \n  Toxicity of high dose is minimal, so it needs more study to test the safe range. \n 314 \n  Ginsenoside RG3, extracted from ginseng, restored TNF‐α‐induced effects by inhibiting NF‐κB, VEGF, and CASP‐3 in EM, which are responsible for cell proliferation, apoptosis, and angiogenesis. \n 79 \n  Ginsenoside PPD regulated ERα and PRα expression to suppress autophagy and lesion growth in EM. \n 103 \n  It also targeted E 2 ‐induced NK cell cytotoxicity to regulate the immune system in EM. \n 103 \n  Ginsenoside also possess synergistic effect with anticancer drugs, as well as prevents toxicity and morbidity from chemotherapy. \n 315 \n  Puerarin is a phytoestrogen, binds to ERs via the ERK pathway to regulate proliferation in EM. \n 93 \n  It also regulates inflammation in ectopic endometrium by inhibiting P450AROM and COX‐2 and promoting ERβ expression to facilitate E 2  metabolism in EM. \n 152 \n  Its therapeutic effects are studied extensively in diseases including cancer and cardiovascular disease. \n 316\nMost of these products have known toxicity or pharmacokinetic profiles and act via multiple targets, making them beneficial as anti‐EM agents. However, their poor aqueous solubility and low oral bioavailability in vivo is the major challenge to be potential EM treatment. 82 ,  92 ,  315  There are several approaches available currently to progress the bioavailability of drugs, which include prodrug approach, \n 130 \n  solid dispersions approach, \n 317 \n  lipid‐based formulation approach. \n 318 \n  On the contrary, the long‐term safety of natural products in reproductive function and EM recurrence profiles should be further elaborated in future studies. Nevertheless, minimal side effects and available as an over‐the‐counter dietary supplement and routine remedies make them preferable to hormonal medicines.\nEM is a complex clinical challenge, and recently, more signaling pathways have been identified to contribute to its pathophysiology. EM drugs that target only one receptor have inadequate therapeutic efficiency. However, although multitarget drugs present potent efficacy in suppressing the progression of EM lesions, they also pose a risk of side effects such as binding to undesirable drug targets and bringing off‐target toxicities. \n 56 \n  Therefore, designing a drug that targets the appropriate pathways with high selectivity is highly desirable. For this purpose, it is essential to understand the compound‐target pathway‐disease relationships.\n\nIn the theory of Chinese medicine, EM is defined as a blood stasis syndrome that leads to the formation of endometriotic lesion and other associated symptoms. Stagnation of Qi (energy) is believed to be one of the causes of EM. TCM aims to lessen the chronic pain experienced by women with EM. Therefore, studies on the action mechanism of TCM are focused mainly on the alleviation of inflammation and oxidation. TCM decoctions containing several herbs in different compositions, which are varied according to the condition of the patient, are a combinational approach that can target various pathophysiology. Fang et al. \n 319 \n  and Tsai et al. \n 320 \n  have identified the decoctions commonly used for treating EM in Taiwan, which included Gui‐Zhi‐Fu‐Ling‐Wan, Dang‐Gui‐Shao‐Yao‐San, Jia‐Wei‐Xiao‐Yao‐San, Shao‐Fu‐Zhu‐Yu‐Tang, and Wen‐Jing‐Tan. The therapeutic efficacy and pathophysiology of TCM in cancer and other diseases have been widely evaluated in vitro and in vivo; however, there are limited studies on the efficacy of TCM for EM.\nMost of the herbs exert anti‐inflammatory effects by inhibiting the production of proinflammatory cytokines. Poria has been confirmed to exert antitumor activities against various cancers. It binds to cytokines and effector immune cells to regulate immunity and upregulate apoptosis. \n 321 \n  Angelicae Sinensis Radix exerts anti‐inflammatory effects by reducing TNF‐α inflammatory cells. \n 322 \n  Ligusticum Rhizoma inhibits inflammation and reduces PGE 2  production. \n 323 \n  Moutan Cortex, Glycyrrhizae Radix, Paeoniae Alba Radix, and Bupleuri Radix suppress proinflammatory cytokines via the NF‐κB signaling pathways. 324 ,  325 ,  326 ,  327  Paeoniae Alba Radix and Bupleuri Radix also exert such effect via MAPK signaling pathways.\nAtractylodis Ovatae Rhizoma exerts antioxidant effect by activating the MAPK cascades and inhibiting the production of radicals by 2,2‐diphenyl‐1‐picrylhydrazyl and catalases, thus inhibiting the activity of free radicals. \n 328 \n  Glycyrrhizae Radix and Poria act as radical scavengers against superoxide and hydroxy radicals. 328 ,  329 ,  330  Ligusticum Rhizoma acts as a reducing agent via the Nrf2 and NF‐κB pathways. \n 331\nAngelicae Sinensis Radix exerts antiproliferative and proapoptotic effects; it induces mitochondrial‐dependent apoptosis and inhibits the Akt/mTOR pathway. \n 332 \n  Atractylodis Ovatae Rhizoma induces apoptosis by upregulating ROS. \n 333 \n  Moutan Cortex exerts proapoptotic effects by increasing Bax/Bcl‐2 expression and decreasing MMP via the formation of apoptosome and cytochrome  c , activation of CASP, and the adenosine monophosphate‐activated protein kinase pathway. \n 323 \n  It also induces apoptosis via activation of CASP‐3/‐8. \n 334 \n  Paeoniae Alba Radix induces apoptosis via activation of CASP‐3/‐9 \n 293 \n  and exerts antiproliferative activity via cell cycle arrest and Fas/Fas ligand‐mediated apoptotic pathway. \n 334 \n  It also downregulates the antiapoptotic protein Bcl and upregulates the apoptotic proteins Bax and CASP‐3. \n 335\nTCMs have great potential as multitarget drugs. As TCMs consist of herbal formulas with various combinations of herbs, they have multiple mechanisms of action, which can be beneficial to reduce the concentration of each herb, thus, drug toxicity. \n 336 \n  However, the costs and availability vary for different herbs, which limits its acceptability in Western countries at present. Furthermore, there is a lack of clinical management methods to evaluate their clinical effectiveness and standardized regulations of TCM practice.\n\nThis is the first review article combining medicinal research based on EM pathophysiology and the related signaling pathways. Our review revealed the challenges in EM management and the need for various available medical treatment options. Most of the medications prescribed by the FDA to treat EM are hormonal, such as contraceptives, progesterone, and GnRH. However, current hormonal medicines raise a major concern in the case of long‐term treatment. Therefore, new nonhormonal pharmaceuticals with relatively safer and few side effects are urgently needed.\nOur aims in this review were to facilitate the research and development of novel treatments for EM based on an understanding of the pathological process. To compare new and old pharmaceuticals, an effective scale to evaluate parameters between different treatments as well as to align outcome measures from preclinical to clinical studies is needed. There is a lack of experimental and clinical evidence to support the effectiveness, pharmacokinetic, and pharmacodynamic profiles of potential drugs in alleviating the pathophysiology of EM, compared with that of drugs already available in the market. Good practices such as the Endometriosis Phenome and Biobanking Harmonization Project, derived by the World Endometriosis Society, can help facilitate a large‐scale collaboration project worldwide. \n 337 \n  It is a platform to ensure that the protocol is sufficient and consistent enough to maintain high research quality, datasets are shared to ensure data reproducibility, and results can better support the development of translational medicine. Moreover, multicenter collaboration can increase research visibility and avoid data integrity issues.\nThe nonhormonal treatments reviewed in this paper were only studied in vitro or in animal models or are still under clinical trials. The drugs mentioned in this review article showed significant efficacy in reducing ectopic endometrium cell viability and endometriotic lesion size; however, severe adverse effects were not elaborated in‐depth. High efficacy and innovative approach do not guarantee final success. Data from legal regulation and patients’ demand for available resources are as important as the pharmacological profile of medicines. In many countries, a new drug must be regulated and approved by the relevant authority before it is launched in the market. \n 338 \n  Thus, apart from efficacy and safety data, the medical and financial burden of EM to women have raised the awareness on EM and accelerated the scientific research on this disease, which are key factors considered by R&D investors. To maximize a drug's value and cost‐effectiveness in the market while maintaining its affordability, fulfilling the society's demand, and making scientific advances, modification of lead compound or bioactive compound derived from natural products holds great potential because only the functional groups are modified, whereas the original core structure is conserved.\nConsidering both the medicinal and commercial perspectives of drug development, there is a huge pressure in the development of a new drug, starting from the synthesis or discovery stage to clinical trial, to proceeding with legal regulations, and to launch in the market. A drug requires 10–17 years of development, with less than 10% success rate to pass clinical trial. \n 339\nTaking advantage of big data mining, drug repurposing is a strategy to identify new therapeutic use of a drug that is approved or under clinical trial, which comprises 30% of newly FDA‐approved drugs and vaccines. 340 ,  341  These drugs can bind to the same target owing to the similar pathophysiology of different diseases, or these drugs can have multiple targets and are thus relevant to other diseases. \n 342 \n  A repurposed drug offers sufficient preclinical pharmacology profile and safety reports, leading to a greater potential for phase III and IV clinical trials, which can reduce the time of drug development and cost of investment. Nevertheless, some advantages of de novo drug development outweigh the benefits of drug repurposing. A constant influx of chemicals via synthesis or extraction from natural products offers novel medical options for patients. A growing understanding of the pathophysiology of EM favors structure‐based or ligand‐based drug designs, in which by modifying lead compounds based on structure–activity relationships, the efficacy, potency, and selectivity can be compromised. However, a more in‐depth research is needed to study the underlying mechanisms and drug targets to support their potential as new EM treatments.\nIn conclusion, this review provides an update on the pathophysiology of EM and shows the efficacy of various medicines in treating EM. Increasing attention has been focused on understanding the pathophysiology of EM and the action mechanisms of potential pharmaceuticals; however, many of these are still not completely understood. With this review, we hoped to raise awareness on the missing puzzle pieces and to promote related research that can further advance diagnosis and treatment for better management of EM and improve the quality of women's lives.\n\nChi Chiu Wang is an active member of the World Endometriosis Society and an advisor of the Aptorum Group.\n\nSze Wan Hung, Ruizhe Zhang, and Chi Chiu Wang participated in research design. Sze Wan Hung participated in data evaluation, extraction and interpretation. Sze Wan Hung, Ruizhe Zhang, and Zhouyurong Tan participated in data validation and in drafting the manuscript. Tao Zhang participated in designing figure 1. Sze Wan Hung, Tao Zhang, Jacqueline Pui Wah Chung and Chi Chiu Wang critically revised the manuscript. All authors approved the final version of the manuscript.","source_license":"CC0","license_restricted":false}