Expression profiles of E-cadherin and N-cadherin in endometriosis and other gynecological diseases towards targeted treatment: a systematic review

Endometriosis is a gynecological disease characterized by the formation of endometrium-like tissue outside the uterus and affects approximately 10% of reproductive-age women [ 1 , 2 ]. Its most prevalent symptoms include chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility, all of which can significantly impair patients’ quality of life [ 3 – 5 ]. Despite extensive research, the causes of endometriosis remain unclear owing to its multifactorial nature [ 6 ]. Common theories such as Sampson’s or stem cell origin theory explain ectopic endometrial tissue, but not its survival [ 7 ]. Critical unresolved issues include the mechanisms through which endometriotic cells trigger inflammation, evade immune detection, and invade tissues and how angiogenesis and fibrogenesis support lesion growth [ 8 – 10 ]. Although benign, endometriosis exhibits neoplastic traits, such as proliferation, apoptosis resistance, angiogenesis, invasiveness, and oncogenic mutations in KRAS, PIK3CA, ARID1A, and CTNNB1 [ 11 – 14 ]. Another shared mechanism between cancer and endometriosis is the epithelial-mesenchymal transition (EMT), in which epithelial cells lose adhesion and gain migratory and invasive properties [ 15 , 16 ]. This systematic review focuses on the disintegration of intercellular junctions, which is a key feature of the EMT. EMT is thought to facilitate endometriotic cell implantation and disease progression [ 17 ]. This process is regulated by hormones, primarily estrogen and 17-β-estradiol. Specifically, the estrogen/ER-α/ERK signaling pathway activates the RhoA/ROCK pathway, thereby driving EMT and supporting endometriotic lesion proliferation. A defining molecular feature of this process is the downregulation of E-cadherin expression in endometriotic cells [ 18 ]. E-cadherin, a transmembrane protein encoded by cadherin 1 (CDH1), is a calcium-dependent adhesion molecule that maintains epithelial cell-cell adhesion and polarity [ 19 ]. Suppression of E-cadherin expression is a key event in the dysfunction of cell-cell adhesion, leading to increased invasiveness and metastasis of tumors, earning E-cadherin the designation of “suppressor of invasion” gene [ 20 ]. Fig. 1 illustrates the structure of E-cadherin, which comprises extracellular, transmembrane, and intracellular domains. The extracellular domain consists of five cadherin modules involved in calcium-mediated intercellular interactions. The transmembrane region anchors the protein to the cell membrane. The intracellular domain interacts with catenins and, through them, with the actin cytoskeleton. Vinculin stabilizes this connection [ 20 , 21 ]. Catenins contribute to the strength of cell-to-cell connections, whereas actin filaments provide mechanical support for the cells and contribute to their movement [ 22 , 23 ]. The functions of E-cadherin can be explained by its involvement in various signaling pathways [ 24 , 25 ], including the Hippo pathway, which modulates cell proliferation and apoptosis through its interaction with yes-associated protein signaling [ 26 , 27 ]. Additionally, E-cadherin is involved in signaling pathways that regulate cellular survival, such as WNT, which participates in the regulation of cellular differentiation and proliferation; nuclear factor κB, which activates inflammation and cellular survival under stressful conditions; mitogen-activated protein kinase, which regulates cell growth and differentiation; and hedgehog, which modulates cellular proliferation and differentiation through the GLI-1 protein [ 28 , 29 ]. Furthermore, through receptor tyrosine kinases, E-cadherin regulates cell adhesion and interaction with the cytoskeleton. E-cadherin also affects the activity of β-catenin, which interacts with T-cell factor and lymphoid enhancer-binding factor-1 to affect the transcription of genes associated with cell proliferation and survival [ 30 , 31 ]. Additionally, E-cadherin modulates cell motility and migration by regulating Rho GTPases (e.g., Rac1 and Cdc42) [ 25 , 32 , 33 ]. Several molecules are associated with E-cadherin during the EMT. A hallmark of this process is the switch from E-cadherin to N-cadherin, which enhances cellular mobility and invasiveness [ 34 , 35 ]. As a result, epithelial cells acquire mesenchymal properties and increase vimentin expression [ 36 – 38 ]. Notably, matrix metalloproteinases (particularly MMP-9) are upregulated, facilitating extracellular matrix degradation [ 39 ]. Transcription factors (e.g., ZEB1, ZEB2, and hypoxia-inducible factor-1α [HIF-1α]) and transcriptional repressors (e.g., TWIST, SNAIL, and SLUG) are also believed to be responsible for EMT initiation [ 36 , 40 – 46 ]. Elevated levels of these molecules, frequently observed in malignancies, are inversely correlated with E-cadherin expression [ 47 , 48 ]. Dysregulation of E-cadherin in endometriosis underscores its dual diagnostic and therapeutic significance [ 31 , 34 , 36 , 37 , 39 – 42 , 49 – 53 ]. Elucidating the role of E-cadherin may uncover novel therapeutic targets and enable non-invasive diagnostic approaches [ 54 ]. Comparative analyses have suggested that endometriosis has a distinct E-cadherin expression profile, intermediate between benign and malignant conditions, which may explain its localized invasive behavior. This systematic review aimed to synthesize the current evidence regarding the role of EMT in the pathogenesis of endometriosis, with a focus on intercellular junction disruption. Specifically, this review explored the contributions of E-cadherin and N-cadherin, as well as their associated signaling pathways and downstream molecular mechanisms.

This systematic review was registered in the National Institute for Health Research International Prospective Register of Systematic Reviews (protocol and registration number: CRD42024561057) and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) guidelines. Institutional Review Board approval was not required because the present study was a review [ 55 ]. Case-controlled, cohort, and cross-sectional clinical trials published in English were included. Case reports, preclinical studies or reviews, opinion articles, and studies published as abstracts were excluded. Proceedings of scientific meetings and abstracts were also excluded. The participants were non-pregnant reproductive-age women with laparoscopically and histologically confirmed endometriosis (endometriosis group) and those with laparoscopic exclusion of endometriosis and histological confirmation of benign/malignant gynecological diseases or exclusion of gynecological pathology (comparison group). The inclusion criteria for the present systematic review were studies reporting original data concerning the evaluation of E-cadherin expression in the ectopic and eutopic endometrium of patients with endometriosis compared to that in the endometrium of patients without endometriosis (i.e., healthy women or patients with other benign/malignant gynecological diseases). The primary outcomes were aimed at assessing the levels of E-cadherin protein or messenger RNA (mRNA) expression in the ectopic and eutopic endometrium of patients with and without endometriosis. The secondary outcomes evaluated the level of factors associated with E-cadherin: N-cadherin, ZEB1 and ZEB2, TWIST, vimentin, SNAIL, SLUG, MMP-9, β-catenin protein or mRNA expression, and the level of HIF-1α protein expression in ectopic and eutopic endometrium of patients with and without endometriosis. Moreover, the correlation of E-cadherin concentration with age, endometrioma size, severity of endometriosis symptoms, and American Society for Reproductive Medicine (ASRM) stage of endometriosis was investigated with respect to the secondary outcomes. An electronic database search was conducted on PubMed, Cochrane Library, ClinicalTrials.gov , Scopus, Embase, and Google Scholar. A combination of the following terms was used: “endometriosis”, “epithelial-mesenchymal transition”, “E-cadherin”, “cadherins”, “pathology”, and “etiology”. The last screening date was April 13, 2025. No restrictions or search filters (publication status, type of article, or language of publication) were applied to verify all potentially relevant studies. Regarding the PubMed electronic database search strategy, the following combinations of keywords were used in the advanced search builder in PubMed: (endometriosis) AND (epithelial-mesenchymal transition) AND (E-cadherin). No filters or limits were applied. As for the Cochrane Library electronic database search strategy, the search combinations were as follows: (endometriosis) AND (epithelial-mesenchymal transition) AND (E-cadherin). No filters or limits were applied. A search was also conducted in the ClinicalTrials.gov electronic database using an advanced search combination: (endometriosis) AND (epithelial-mesenchymal transition) AND (E-cadherin). Additionally, a search was conducted using MeSH terms in PubMed (“Endometriosis”[Mesh]) AND (“Epithelial-Mesenchymal Transition”[Mesh]) AND (“Cadherins”[Mesh]) and in the Cochrane Library (MeSH descriptor: [Endometriosis] explode all trees and with qualifier(s): [etiology-ET, pathology-PT]). The search was conducted independently by three investigators (L.O., K.K., and E.P.). The search results were saved in a reference manager (Zotero version 6.0.8; Corporation for Digital Scholarship, Vienna, VA, USA). After searching, all articles were reviewed based on their titles and abstracts. The full text of each potentially relevant study was obtained and independently assessed for inclusion by the authors. Additionally, a manual search of the references of the articles was performed to identify additional studies of interest. Any disagreements regarding the inclusion or exclusion of preselected studies and any other disagreements during the review process were resolved with the help of a fourth author (L.P.). A risk-of-bias assessment was performed for each of the included studies using Cochrane Collaboration tools and the Cochrane Handbook for Systematic Reviews of Interventions [ 56 ]. Three authors independently evaluated the quality of the selected studies (L.O., K.K., and E.P.). Any discrepancies between the reviewers were resolved through discussion or consultation with the fourth review author (L.P.). Following the Cochrane Handbook for Systematic Reviews of Interventions, risk of bias in non-randomised studies-of interventions (ROBINS I) was used for nonrandomized studies. Additionally, these tools were used to assess the risk of bias arising from reporting bias due to missing synthesis results [ 57 ].

Fig. 2 shows the PRISMA flow diagram presenting the entire search strategy and results. The initial search yielded 189 articles. After the MeSH search, 215 reports were identified: 87 from PubMed and 128 from the Cochrane Library. After removing duplicates and searching the titles and abstracts of the articles, 267 publications were selected. Consequently, 92 reports remained for full-text screening and analysis based on the inclusion criteria. Seventy reports did not meet the inclusion criteria due to reasons detailed in Fig. 2 and were thus excluded. Out of these 70 studies, nine were eliminated because of their ineligible designs, and 12 studies did not include a comparison group. Additionally, 30 studies assessed another outcome. Moreover, among the 70 reports, four articles were not written in the English language, five reports had no available full text, eight studies did not meet the inclusion criteria, and two studies were outdated. A list of the excluded studies is provided in the supporting information ( Supplementary Table 1 ). Additionally, 1,134 articles were found in the references of 22 articles included in the qualitative analyses. However, none of these studies were included in the systematic review because most were duplicates of articles found earlier or assessed other outcomes. Therefore, 23 studies were retained for qualitative synthesis [ 17 , 34 – 37 , 40 – 42 , 49 – 53 , 58 – 67 ]. The characteristics of the included studies are summarized in Table 1 . Verification of the diagnosis in the studied groups is presented in Table 2 , and the methods for collecting the biosamples and evaluating the expression of the investigated molecules are described in Table 3 . Three reviewers (L.O., K.K., and E.P.) independently assessed the risk of bias in each of the included studies using ROBINS I for nonrandomized studies, in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Any disagreements were resolved through discussion with the fourth author (L.P.). The visualization tools were created using the risk of bias visualization app [ 64 ]. This application created “traffic light” graphs of domain-level judgments for each result and weighted bar graphs of the distribution of risk-of-bias judgments within each bias domain. Based on these tools, the included trials had moderate, serious, and critical risks of bias ( Fig. 3 ). E-cadherin levels were assessed using two complementary approaches: immunohistochemical analysis of E-cadherin protein expression and quantitative measurement of E-cadherin mRNA expression. The experimental group comprised 977 samples of patients with endometriosis, whereas the comparison group consisted of patients without endometriosis, including samples from the healthy comparison group (n=205) and patients with benign gynecological diseases (n=73), unexplained (n=98) or tubal infertility (n=34), and malignant diseases such as cervical intraepithelial neoplasia (n=21), endometrial (n=32), and ovarian carcinoma (n=36). The difference in E-cadherin protein expression between patients with endometriosis and the comparison group was evaluated in nine studies [ 34 – 36 , 41 , 52 , 60 , 62 , 64 , 67 ]. Six of these studies reported significantly reduced E-cadherin expression in both ectopic and eutopic endometrium compared to controls ( P <0.01) [ 36 , 41 , 52 , 62 , 64 , 67 ]. This finding was corroborated by Yu et al. [ 34 ] and Sancakli Usta et al. [ 35 ] who observed lower E-cadherin levels in ectopic lesions ( P =0.006 and P <0.001, respectively). However, the difference between its expression between the eutopic endometrium and the comparison group was controversial: Sancakli Usta et al. [ 35 ] did not show a significant difference, but in the study by Yu et al. [ 34 ], the eutopic endometrium of patients with endometriosis presented higher expression of E-cadherin than the comparison group. Three studies [ 34 , 52 , 67 ] directly compared ectopic and eutopic endometrium, uniformly demonstrating lower E-cadherin expression in the lesions ( P <0.05). Notably, Matsuzaki et al. [ 60 ] identified menstrual cycle-dependent variations with no significant differences in the proliferative/early-secretory phases, but elevated expression in the mid-secretory phase ( P <0.0001) and reduced levels in the late secretory phase ( P <0.05) in patients. The difference in E-cadherin mRNA expression between patients with endometriosis and the comparison group was evaluated in three studies; however, the outcomes were controversial [ 41 , 60 , 63 ]. Lin et al. [ 41 ] reported decreased E-cadherin mRNA levels in endometriosis ( P <0.001), Saare et al. [ 63 ] observed the opposite pattern ( P <0.001), and Matsuzaki et al. [ 60 ] reported no significant differences. Differences in E-cadherin protein expression between patients with endometriosis and patients with uterine fibroids were evaluated in three studies [ 37 , 50 , 60 ]. The outcome was quite controversial: Biyik et al. [ 50 ] reported that patients with endometriosis had lower E-cadherin expression levels than patients with uterine fibroids and that E-cadherin levels were higher in ovarian endometriomas than in deep infiltrative endometriosis lesions. The results of Matsuzaki et al. [ 60 ] are similar to those described in the previous section. E-cadherin mRNA expression in patients with endometriosis and uterine fibroids was assessed in two studies [ 53 , 60 ]. Zubrzycka et al. [ 53 ], study presented a significantly lower expression of E-cadherin in ectopic lesions than in patients with uterine fibroids ( P <0.05); however, Matsuzaki et al. [ 60 ], study hasn’t obtained a significant difference. Moreover, Zubrzycka et al. [ 53 ] observed no significant difference between the eutopic endometrium of patients with endometriosis and that of patients with uterine fibroids ( P <0.09). Four studies compared E-cadherin expression in endometriosis and benign gynecological conditions [ 35 , 39 , 49 , 58 ]. Furuya et al. [ 58 ] and Wu et al. [ 39 ] demonstrated significantly lower E-cadherin levels in the ectopic and eutopic endometrium of patients with endometriosis compared to those of patients with other benign diseases ( P <0.05), with a particularly pronounced reduction in deep infiltrating endometriosis compared to ovarian endometriosis. Nevertheless, Liu et al. [ 49 ] reported no significant difference in expression between the deep infiltrating, peritoneal, and ovarian endometriosis groups. E-cadherin expression in the ectopic endometrium, compared to that in the normal endometrium, was decreased in both Liu et al. [ 49 ] and Sancakli Usta et al. [ 35 ]. In addition, its expression was presented to be lower in ectopic lesions than in eutopic endometrium ( P <0.05) [ 49 ]. However, no difference in expression was observed between the eutopic endometrium of patients with endometriosis and a control group [ 35 ]. Two studies reported conflicting results regarding E-cadherin expression in endometriosis and endometrial carcinoma [ 40 , 64 ]. Markov et al. [ 40 ], study presented a higher level of E-cadherin expression in endometrial carcinoma than in endometriosis ( P <0.005). But at the same time, Shaco-Levy et al. [ 64 ], study showed the exact opposite outcome ( P <0.001). Similarly, discordant results emerged from two studies comparing endometriosis and ovarian carcinoma [ 40 , 51 ]. Thus, in Markov et al. [ 40 ], study, the level of E-cadherin expression was lower in the endometriosis group ( P <0.005), but in Păvăleanu et al. [ 51 ], study the level was lower in patients with ovarian carcinoma ( P =0.001). The difference in E-cadherin protein expression between patients with endometriosis and cervical intraepithelial neoplasia was evaluated by Meng et al. [ 37 ], who showed that E-cadherin expression in ectopic lesions was significantly lower than that in the eutopic endometrium and endometrium of the control group ( P <0.01). Two studies assessed E-cadherin protein expression in patients with endometriosis and unexplained infertility [ 42 , 60 ]. Li et al. [ 42 ] concluded that patients with endometriosis presented lower E-cadherin expression than patients with unexplained infertility ( P <0.05). Matsuzaki et al. [ 60 ] also presented that in the late-secretory phase, E-cadherin expression was lower in the endometriosis group ( P <0.05); however, in the middle-secretory phase, the level of E-cadherin expression was higher ( P <0.0001) in patients with endometriosis, but in the early secretory and proliferative phases of the menstrual cycle, the difference was insignificant. E-cadherin mRNA expression in patients with endometriosis and unexplained infertility was assessed in four studies [ 17 , 42 , 60 , 65 ]. Two of them presented reduced expression of E-cadherin in both the ectopic and eutopic endometrium of patients with endometriosis, with a statistically significant difference ( P <0.001) [ 17 , 65 ]; however, Matsuzaki et al. [ 60 ] showed that the difference was not statistically significant. Moreover, Li et al. [ 42 ] reported that E-cadherin expression in the eutopic endometrium was higher than that in the ectopic endometrium but lower than that in patients without endometriosis ( P <0.01). The difference in E-cadherin protein expression between patients with endometriosis and tubal infertility was investigated in a study by Liu et al. [ 59 ], which showed that patients with ovarian endometrioma presented a statistically significant decrease in E-cadherin expression in both eutopic and ectopic endometrium ( P <0.05). Moreover, its expression level was significantly higher in the eutopic endometrium than in the ectopic endometriotic lesions ( P <0.05). Differences in N-cadherin protein expression between patients with and without endometriosis were evaluated in seven studies [ 34 , 39 , 41 , 42 , 49 , 62 , 67 ]. Five of these studies reported higher levels of expression in both ectopic and eutopic samples from patients with endometriosis [ 39 , 41 , 42 , 49 , 62 ]. However, contradictory findings emerged: Xiong et al. [ 67 ] observed higher N-cadherin levels in the ectopic lesions but lower N-cadherin levels in the eutopic endometrium of patients with endometriosis than in the comparison group ( P <0.05), whereas Yu et al. [ 34 ] found lower expression in ectopic lesions than in the comparison group ( P <0.001), with no difference observed between the eutopic endometrium of patients with endometriosis and the comparison group. Discrepancies also existed in ectopic-eutopic comparisons; Xiong et al. [ 67 ] reported higher expression in ectopic samples ( P <0.05), whereas Yu et al. [ 34 ] demonstrated the opposite pattern. The difference in N-cadherin mRNA expression between patients with and without endometriosis was evaluated in three studies, all of which demonstrated significantly increased N-cadherin mRNA levels in both ectopic and eutopic samples from patients with endometriosis ( P <0.01) [ 41 , 42 , 65 ]. Expression patterns of β-catenin, ZEB1, ZEB2, TWIST, vimentin, SNAIL, SLUG, MMP-9, and HIF-1α are detailed in the supporting information ( Supplementary Material 1 ).

This review evaluated the expression patterns of E-cadherin, N-cadherin, β-catenin, and other EMT markers across endometriosis, gynecological diseases, and healthy controls using immunohistochemical, Western blot, and polymerase chain reaction (PCR) analyses of ectopic and eutopic endometrium. We identified significant correlations between E-cadherin expression and clinical parameters including age, endometrioma size, symptom severity, and ASRM stage ( Table 1 ). Some studies showed reduced E-cadherin expression in ectopic and eutopic endometrium of patients with endometriosis compared with its expression in endometrium of patients without endometriosis (healthy comparison group and patients with non-malignant gynecological diseases) [ 17 , 34 – 36 , 39 , 41 , 42 , 49 , 50 , 52 , 53 , 58 – 60 , 62 , 64 , 65 , 67 ]. Moreover, some of the included studies reported higher E-cadherin concentration in endometriotic lesions than in the eutopic endometrium of patients with endometriosis [ 34 , 35 , 37 , 42 , 49 , 52 , 53 , 59 , 67 ]. Similar results were obtained for β-catenin concentration [ 39 , 51 , 64 , 65 , 67 ]. On the contrary, some studies revealed that the expression levels of N-cadherin [ 34 , 41 , 42 , 49 , 52 , 62 , 65 , 67 ], ZEB1 and ZEB2 [ 34 , 41 , 58 ], TWIST [ 17 , 42 ], vimentin [ 36 , 37 , 41 , 59 , 62 , 65 , 67 ], SNAIL [ 17 , 62 , 65 ], SLUG [ 17 , 62 ], MMP-9 [ 39 , 64 ], and HIF-1α [ 36 , 40 , 59 , 67 ] were higher in patients with endometriosis. In addition, the E-cadherin concentration in patients with ovarian and endometrial carcinomas was lower than that in patients with endometriosis [ 40 , 51 , 64 ]. These findings support the development of therapies targeting cell adhesion and invasion in endometriosis. Reduced E-cadherin expression in ectopic lesions supports EMT, representing an intermediate state between benign (high E-cadherin expression) and malignant conditions (low E-cadherin expression) [ 24 ]. Concurrently, β-catenin levels are diminished, while mesenchymal markers (N-cadherin, vimentin) [ 68 – 70 ] and EMT-inducing factors (ZEB1/2, TWIST, SNAIL, SLUG, and HIF-1α) are upregulated [ 43 – 45 , 71 – 73 ]. These molecular shifts correlated with increased MMP activity, facilitating basement membrane degradation and ectopic cell invasion [ 74 ]. Collectively, progressive E-cadherin/β-catenin loss and reciprocal upregulation of EMT-associated molecules underscore the dynamic inverse relationship that drives disease progression. While systematic reviews on this subject are lacking, Yin et al. [ 13 ], Lessey and Young [ 75 ], and Nasu et al. [ 76 , 77 ] reported E-cadherin downregulation in endometriosis. However, Starzinski-Powitz et al. [ 78 ] did not confirm the lack of E-cadherin expression in endometriosis. Decreased E-cadherin expression in endometriosis highlights its therapeutic potential as a monoclonal antibody (mAbs) activates E-cadherin to suppress metastasis in breast cancer models. These antibodies increase cell adhesion and reduce cell movement, thereby blocking tumor invasion, intra-and extravasation, and the ability of cancer cells to establish colonies and form distant metastases. The activation of E-cadherin by mAbs may induce tumor cell apoptosis via changes in the adhesion and activation of signaling pathways, including the Hippo and PI3K/AKT pathways [ 79 ]. Additionally, the number of circulating tumor cells in the blood is reduced. Because of their high efficacy in controlling metastasis, these antibodies may also have therapeutic potential in endometriosis [ 80 ]. Notably, in a mouse model of inflammatory bowel disease, restoration of E-cadherin expression using monoclonal antibodies suppressed pro-inflammatory cascades and attenuated disease progression, suggesting its potential applicability in endometriosis [ 32 ]. Histone deacetylase inhibitors (HDACIs) can restore E-cadherin expression by reactivating CDH1 transcription. Previous studies demonstrated that trichostatin A and valproic acid attenuate the invasive potential of endometrioid cells by upregulating E-cadherin mRNA and protein expression. Furthermore, experimental research conducted by Guo [ 14 ] in rodent models of endometriosis revealed that administration of these agents reduced the size of endometriotic lesions and alleviated pain in animals with induced endometriosis [ 66 , 81 – 83 ]. The efficacy of HDACIs has been actively investigated in malignancies characterized by E-cadherin loss, including endometrial, breast, and gastric cancers. In such studies, HDACI treatment restored physiological E-cadherin expression levels with concomitant decreases in cellular invasiveness, motility, and metastatic potential [ 84 , 85 ]. Notably, HDACIs can reactivate E-cadherin expression by inhibiting its transcriptional repressors such as TWIST, SNAIL, and ZEB1/2. This mechanism has been reported by Yang et al. [ 86 ], by the application of vorinostat in a breast cancer model, stabilized the epithelial phenotype of the tumor and inhibited cell motility. Although the data presented above are experimental and have not been validated through clinical studies, they may represent a potential area for further investigation in future research. The strength of our study is the comprehensive analysis of all available data assessing EMT processes and cadherin-associated pathways in the pathogenesis of endometriosis. We conducted the first systematic review of all currently available data describing the impaired expression of E-cadherin in both the eutopic endometrium and ectopic lesions of patients with endometriosis, in comparison with the level of E-cadherin expression in the endometrium of patients without endometriosis (healthy comparison group and patients with other benign or malignant gynecological diseases). Unlike previous reviews that primarily focused on individual biomarkers or specific signaling pathways, our systematic review comprehensively integrated data on E-cadherin, N-cadherin, β-catenin, and associated molecules across various gynecological conditions. This holistic approach provides a broader understanding of the molecular mechanisms underlying the progression of endometriosis and highlights potential diagnostic and therapeutic targets. The practical significance of this study lies in the potential use of cadherins and their associated factors as biomarkers for early and non-invasive diagnosis of endometriosis, which could accelerate diagnosis and improve disease prognosis. Moreover, the findings of this review emphasize the need for targeted therapy aimed at modulating EMT processes in endometriotic lesions. However, this study has some limitations. First, studies comparing the expression of E-cadherin and other molecules in patients with endometriosis and healthy individuals are currently insufficient. Therefore, in our study, we considered the differences in molecular expression between patients with benign and malignant gynecological conditions. To gain a comprehensive understanding of the role of E-cadherin in the pathogenesis of endometrial diseases, studies that include patients with benign endometrial diseases are necessary. In addition, some of the included articles had a critical and serious risk of bias owing to their low quality. Moreover, some studies assessed only mRNA levels, whereas others evaluated only the protein expression of the investigated biomarkers. Several articles failed to provide numerical values for mRNA or protein expression of the assessed molecules, or omitted specifications of benign diseases affecting the comparison group patients. In addition, the methods of diagnostic verification, collection of biopsy samples, and evaluation of the expression of the investigating molecules were different in the included papers. Furthermore, some authors have not provided such information, which makes it difficult to draw conclusions regarding the quality of the studies under review, as indicated in Tables 2 , 3 . In conclusion, some studies divided patients into groups based on the phase of their menstrual cycles, whereas the remaining studies did not provide relevant information. It is also impossible to mention the high heterogeneity in the study groups. Additionally, the data from the included studies were not presented as absolute values, but rather as relative values, which made them unsuitable for objective statistical analysis. The inconsistent reports on E-cadherin across studies likely reflect methodological and biological variables. Immunohistochemistry (IHC)-based protein detection captures functional adhesion loss more reliably than mRNA analysis, which can be influenced by non-epithelial cells. Furthermore, the menstrual cycle phase and endometriosis subtype (e.g., deep infiltrating endometriosis vs. peritoneal) critically affected expression. Future studies should standardize sampling protocols and stratify analyses based on these factors. The variability in E-cadherin measurements may stem from unaccounted cycle phases, subtype heterogeneity, or technical differences (IHC antibodies and PCR primers). Although we excluded studies without histological confirmation, confounding factors precluded definitive quantitative comparisons. Based on the above limitations, some of the results obtained are contradictory. Implications for future research may include conducting studies with larger numbers of participants, taking into account the form and stage of endometriosis, the phase of the menstrual cycle, as well as the treatment of patients, assessing both mRNA and protein expression in eutopic and ectopic endometrium of patients with endometriosis, and comparing the results with their levels in healthy fertile women of reproductive age without any concomitant pathology. Conducting a comprehensive meta-analysis of data from these studies is necessary to objectively identify differences in the expression levels of these molecules in the patient groups under investigation. Moreover, studies measuring the E-cadherin concentration in the peripheral blood of patients are required for the possible use of E-cadherin as a non-invasive biomarker of endometriosis. Conducting experimental studies on E-cadherin reactivation in endometrioid cells is also necessary. It is important to test existing drugs that target tumor cells in endometriosis models and to search for new molecules that can help restore E-cadherin function. These drugs may reduce the risk of endometriotic tissue spread and possibly slow its progression. It is equally important to work towards improving the quality of research on endometriosis within the framework of evidence-based medicine, which includes the development of more appropriate animal models, the adoption of integrative and multidisciplinary research approaches, adherence to rigorous publication and reporting standards, and the standardization of surgical techniques. The aim of numerous scientific studies is to develop a personalized multidisciplinary approach for the treatment of endometriosis that integrates surgical intervention, including the management of adhesions, hormonal therapy, and rehabilitation programs designed to restore the lost quality of life of patients [ 87 ]. It is equally important to establish an early and non-invasive diagnosis of endometriosis, minimize the time between manifestation and detection of the disease, and prevent the progression of the condition to more advanced stages. This systematic review comprehensively evaluated the role of cadherins and their associated molecular pathways in the pathogenesis of endometriosis. The dysregulation of E-cadherin and N-cadherin expression provides robust experimental support for the transplantation theory of endometriosis development and progression. These findings underscore the therapeutic potential of targeting cadherin-mediated signaling pathways to develop novel treatment strategies for this condition.