Multi-Target Modulation of Interconnected Pathogenetic Pathways by Natural Bioactive Compounds in Endometriosis

Kamila Pokorska-Niewiada, Małgorzata Szczuko, Khasan Kayumov, Katarzyna Janda-Milczarek
Antioxidants (Basel, Switzerland) · 2026 · vol. 15(8) , pp. 1003 · doi:10.3390/antiox15081003 · PMID:42650267 · PMC13509593 · W7202344272
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This integrative review summarizes how natural bioactive compounds like curcumin and resveratrol modulate multiple interconnected pathogenic pathways in endometriosis, highlighting their potential as adjunctive therapies despite limited clinical evidence.

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This integrative review examines the multifactorial pathogenesis of endometriosis, focusing on interconnected molecular pathways such as inflammation, angiogenesis, oxidative stress, and hormonal signaling. It evaluates how natural bioactive compounds may offer therapeutic potential by simultaneously modulating multiple targets within these complex networks, including NF-κB, HIF-1α, and estrogen receptors. The authors note that while experimental evidence supports these mechanisms, clinical data remains limited, necessitating further studies to establish efficacy and safety. This paper is centrally about endometriosis — specifically exploring the role of natural bioactive compounds in modulating its underlying pathogenetic pathways.

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Abstract

BACKGROUND: Endometriosis is a chronic estrogen-dependent disease characterized by the presence of endometrial-like tissue outside the uterine cavity. Its pathogenesis involves interactions between inflammatory, angiogenic, hormonal, oxidative stress-related, and cell survival-associated pathways, contributing to lesion development and persistence. Current treatment options are often limited by adverse effects, incomplete symptom control, and high recurrence rates. METHODS: This integrative review summarizes the molecular mechanisms involved in endometriosis and the potential role of natural bioactive compounds in their modulation. A literature search was conducted using PubMed, Scopus, and Web of Science, and evidence from experimental, animal, and clinical studies was reviewed. RESULTS: Natural compounds such as curcumin, resveratrol, quercetin, EGCG (epigallocatechin-3 gallate) and genistein have been reported to modulate multiple pathways involved in endometriosis. Their biological activity includes modulation of inflammatory signaling, angiogenesis, estrogen-dependent processes, epithelial-mesenchymal transition, oxidative stress, and apoptosis. While some compounds influence several interconnected pathways, others appear to exert more selective effects. CONCLUSIONS: The findings summarized in this review suggest that natural bioactive compounds may influence several interconnected mechanisms involved in endometriosis. Although clinical evidence remains limited, these compounds warrant further investigation as potential adjuncts to current therapeutic approaches.
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Section 2

A literature search was conducted using the PubMed, Scopus, and Web of Science databases to identify studies related to natural bioactive compounds and endometriosis. Articles published up to July 2026 were considered. Search terms combined keywords related to endometriosis (“endometriosis”), natural bioactive compounds (“natural compounds”, “bioactive compounds”, “polyphenols”, “flavonoids”), and the main molecular mechanisms involved in disease pathogenesis, including inflammation, oxidative stress, angiogenesis, estrogen signaling, epithelial–mesenchymal transition, and apoptosis. Boolean operators (AND, OR) were used to refine the search strategy. The reference lists of relevant articles were also screened to identify additional studies. Original in vitro, animal, and clinical studies investigating the biological activity of natural bioactive compounds in endometriosis were included. Review articles were used primarily to provide background information and to identify additional original studies. Only articles published in English were considered. Conference abstracts, editorials, case reports, duplicate publications, and studies unrelated to the scope of this review were excluded. Titles and abstracts retrieved from the database search were screened to identify studies relevant to the scope of this review. Potentially eligible articles were then assessed in full. Studies investigating the molecular mechanisms involved in endometriosis or the biological effects of natural bioactive compounds on disease-related pathways were included. Conference abstracts, editorials, case reports, duplicate publications, and studies outside the scope of the review were excluded. The selected studies were reviewed to extract information relevant to the objectives of this review. This included the investigated compound, its chemical class, experimental model, molecular targets and signaling pathways, biological effects, proposed mechanisms of action, available clinical evidence, and major translational limitations, including reported strategies to improve bioavailability. The extracted information was organized into summary tables and integrated into the narrative synthesis presented in this review. The available evidence was synthesized qualitatively with emphasis on the major molecular mechanisms involved in the pathogenesis of endometriosis and their modulation by natural bioactive compounds. Findings from experimental and clinical studies were analyzed together to identify common molecular targets, biological effects, and potential mechanisms of action. To facilitate comparison, the reviewed compounds were classified into three groups according to the breadth of their reported activity across the major pathogenetic pathways discussed in this review. This classification was introduced solely to organize the available evidence and should not be interpreted as a ranking of therapeutic efficacy, clinical relevance, or the strength of the available evidence. Owing to the diversity of the included studies, no formal quality assessment or quantitative synthesis was performed.

Section 3

The pathogenesis of endometriosis involves multiple interconnected molecular pathways rather than a single dominant mechanism. Processes such as inflammation, oxidative stress, angiogenesis, hormonal signaling, and impaired cell survival collectively contribute to the development and persistence of lesions. Understanding these pathways as components of a broader interacting network is essential for identifying potential therapeutic targets, particularly in the context of the multitarget approaches discussed later [ 15 , 16 ]. Although discussed separately, these mechanisms are functionally interconnected and collectively contribute to lesion development and persistence. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway is one of the key regulators of the inflammatory response in endometriosis, integrating signals originating from oxidative stress and the cytokine milieu. Its activation, induced by ROS (reactive oxygen species) and pro-inflammatory cytokines, leads to increased expression of inflammatory mediators such as IL-6, TNF-α, and COX-2, thereby sustaining chronic inflammation [ 3 , 17 , 18 ]. Activation of NF-κB not only intensifies the inflammatory response but also affects fundamental cellular processes, including cell proliferation, survival, and invasiveness of endometrial cells. At the same time, inhibition of apoptosis is observed, thereby contributing to the persistence of ectopic lesions [ 19 , 20 ]. Of particular importance is the interaction between NF-κB and estrogen signaling. Estrogen may enhance the activity of this pathway, leading to further amplification of the inflammatory response and establishing a self-perpetuating regulatory loop. From a therapeutic perspective, NF-κB represents an attractive target for bioactive compounds that, through anti-inflammatory and antioxidant effects, may limit the activity of this pathway and its biological consequences [ 21 , 22 , 23 , 24 , 25 ]. Beyond its role in inflammation, NF-κB interacts with pathways involved in angiogenesis, estrogen signaling, and cell survival, highlighting its importance in the complex molecular landscape of endometriosis. Angiogenesis plays a key role in the development and maintenance of endometrial lesions by ensuring an adequate supply of oxygen and nutrients. This process is particularly enhanced under conditions of local hypoxia, a hallmark of the endometriotic microenvironment. In response to hypoxia, HIF-1α is stabilized and regulates the expression of numerous proangiogenic genes, including vascular endothelial growth factor (VEGF). Acting through vascular endothelial growth factor receptor 2 (VEGFR2), VEGF stimulates endothelial cell proliferation and migration, as well as the formation of new blood vessels. Newly formed vessels often exhibit an immature structure and increased permeability, which promotes the persistence of inflammation and further lesion progression [ 15 , 16 , 26 ]. Angiogenesis is closely linked to other processes involved in endometriosis, particularly inflammation and hypoxia, which together contribute to lesion maintenance and progression. Estrogen signaling is an important component of endometriosis pathogenesis, with particular emphasis on estrogen receptor beta (ERβ) overexpression and disruption of the balance between estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). A key mechanism involves increased aromatase activity, leading to local estrogen production within endometrial tissues. As a result, elevated estrogen levels are maintained, thereby promoting cell proliferation and lesion persistence. Estrogen signaling is closely linked to inflammation. Estrogen may enhance NF-κB activity, which in turn increases the expression of inflammatory mediators and enzymes involved in estrogen synthesis, creating a positive feedback loop. Natural bioactive compounds may modulate this axis through the regulation of estrogen receptors and steroidogenic enzymes, making it an important therapeutic target [ 9 , 27 , 28 , 29 , 30 , 31 , 32 ]. Through its interactions with inflammatory and proliferative pathways, estrogen signaling contributes to several key processes involved in lesion development and persistence. Epithelial–mesenchymal transition (EMT) is a key mechanism that enables endometrial cells to acquire migratory and invasive properties. This process is initiated, among others, by TGF-β, which leads to the loss of epithelial characteristics and increased cellular motility. The regulation of this process involves transcription factors such as Snail and Slug, which control the transition toward a mesenchymal phenotype. Cellular invasion is further supported by extracellular matrix degradation mediated by metalloproteinases, particularly MMP-2 and MMP-9, enabling tissue penetration and the formation of ectopic lesions [ 33 , 34 , 35 , 36 ]. More specialized regulators have also been implicated, including miR-34c-5p, miR-141, ILK, eIF3e, and the TGF-β1/SMAD2 axis, as well as biological factors such as melatonin and LXA4, which may modulate the course of EMT [ 37 , 38 ]. Taken together, these observations indicate that EMT is regulated by several molecular mechanisms acting at different stages of lesion development. Endometrial cells in endometriosis show an increased ability to evade apoptosis, enabling their survival and accumulation in ectopic locations. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) pathways play a key role in this process by promoting cell proliferation while inhibiting mechanisms leading to cell death. Imbalances between pro- and anti-apoptotic proteins, such as Bax and Bcl-2, together with reduced caspase-3 activity, further promote the persistence of pathological cells [ 24 , 39 , 40 , 41 ]. Disruption of apoptotic pathways contributes to prolonged cell survival and resistance to programmed cell death, facilitating the persistence of ectopic endometrial tissue [ 29 , 42 , 43 , 44 ]. These alterations are closely linked to other pathogenic processes involved in endometriosis, including inflammation, oxidative stress, and aberrant cellular proliferation. The mechanisms described above do not function independently but form a complex, interconnected regulatory network. The NF-κB–HIF-1α–VEGF axis plays a particularly important role by integrating inflammatory signals, hypoxia, and angiogenic processes. Activation of NF-κB increases the expression of inflammatory mediators, which may enhance hypoxia-inducible factor 1-alpha (HIF-1α) stabilization under hypoxic conditions. HIF-1α, in turn, induces VEGF expression, promoting angiogenesis and the formation of new blood vessels [ 22 , 45 , 46 , 47 ]. The resulting vascular network facilitates further recruitment of inflammatory cells and maintenance of the inflammatory microenvironment, thereby promoting positive feedback loops. These processes are additionally modulated by estrogen signaling, as well as mechanisms associated with EMT and cell survival [ 48 ]. Together, these observations highlight the close relationship between inflammation, hypoxia, angiogenesis, and other processes involved in lesion persistence.

Section 5

Endometriosis is increasingly understood not as a result of a single dysregulated pathway, but rather as a condition driven by a network of interacting processes. Inflammation, oxidative stress, angiogenesis, estrogen signaling, epithelial–mesenchymal transition (EMT), and impaired apoptosis are closely linked and tend to reinforce each other, contributing to the persistence of lesions [ 10 , 49 ]. Within this context, natural bioactive compounds do not act on one target only. Many of them influence several key regulatory points at the same time, including NF-κB, HIF-1α, VEGF, and estrogen-related pathways. As a result, these compounds may influence several interconnected pathways rather than a single molecular target. For instance, changes in NF-κB activity can affect both inflammatory signaling and angiogenesis, while oxidative stress may influence apoptosis as well as hormone-related pathways. As a result, the effects of bioactive compounds often overlap across different levels of regulation [ 214 , 220 ]. The interactions between these pathways are dynamic rather than independent. Because these pathways are interconnected, modulation of one pathway may also influence other processes involved in lesion maintenance. Inflammation may increase oxidative stress and angiogenic signaling, whereas hypoxia promotes HIF-1α activation and VEGF expression. In turn, these changes help maintain the local environment that supports lesion growth and persistence, creating positive feedback loops that further sustain the disease process. The relative contribution of these pathways may also vary depending on the local microenvironment and the biological characteristics of individual lesions [ 10 , 49 ]. Not all compounds discussed in this review appear to act with the same breadth of activity. While some, such as curcumin, resveratrol, quercetin, EGCG, genistein, puerarin, and ginsenosides, have been associated with effects across several pathogenetic pathways, others appear to exert more selective actions. Examples include daidzein, which primarily affects estrogen-dependent mechanisms, xanthohumol, which has been studied mainly in the context of angiogenesis, and luteolin, whose reported activity is largely related to inflammatory signaling. This diversity suggests that natural compounds may differ not only in their molecular targets but also in their potential role within multi-target therapeutic strategies. From this perspective, their role may be better understood in terms of modulation rather than inhibition. Instead of blocking a single pathway, these compounds may influence several interconnected processes, potentially weakening the feedback mechanisms that sustain lesion persistence. In a heterogeneous and multifactorial disease such as endometriosis, this broader mode of action may be particularly relevant.

Section 6

The available evidence on natural bioactive compounds in endometriosis remains dominated by in vitro and animal studies. Although these studies have provided valuable insights into the molecular mechanisms involved in disease progression, their findings cannot be directly translated into clinical practice. Human studies remain limited, and despite the growing number of preclinical studies, clinical data are still scarce for most compounds. Interpretation of the current literature is further complicated by substantial differences in experimental design. Studies vary with respect to model systems, treatment duration, administered doses, and evaluated outcomes, making direct comparisons difficult. In addition, the level of evidence is not uniform across compounds. While some, such as curcumin, resveratrol, quercetin, and EGCG, have been investigated extensively, others are supported by only a limited number of studies. Moreover, differences in experimental models, treatment protocols, and outcome measures make it difficult to compare the reported effects across studies. Consequently, apparent differences in efficacy between compounds may partly reflect methodological variability rather than true differences in biological activity. Another challenge concerns the pharmacokinetic properties of many natural compounds. Poor bioavailability, rapid metabolism, limited absorption, and low tissue concentrations remain important barriers to clinical application. As a result, biological effects observed under experimental conditions may not always be achievable in vivo [ 10 , 14 , 50 ]. Future studies should focus on strengthening the clinical evidence base and improving the comparability of experimental findings. Another challenge is the lack of standardized outcome measures across studies. Future research would benefit from the use of validated biomarkers related to inflammation, angiogenesis, oxidative stress, and hormonal signaling, including NF-κB, TNF-α, IL-6, VEGF, and estrogen receptor-associated pathways. Such approaches may facilitate comparisons between studies and improve the evaluation of treatment responses. Further work is also needed to evaluate formulation strategies designed to enhance bioavailability. Future studies should also explore the potential of combination approaches involving natural bioactive compounds and established pharmacological therapies. Such strategies may provide broader modulation of interconnected pathogenetic pathways than single-agent interventions. However, little is known about potential interactions with commonly used treatments, including hormonal therapies and nonsteroidal anti-inflammatory drugs. Further studies are needed to clarify these interactions. Further investigation of interactions between inflammatory, angiogenic, hormonal, and cell survival pathways may help identify the most promising therapeutic targets. The effectiveness of natural bioactive compounds may also differ according to lesion phenotype, disease stage, and individual patient characteristics, highlighting the need for more personalized approaches in future research. Greater methodological consistency across future studies would facilitate comparison of results and strengthen the available evidence.

Intro

Endometriosis is a chronic and often debilitating disease affecting approximately 10–15% of women of reproductive age; nevertheless, it remains underdiagnosed and inadequately treated. Beyond its clinical manifestations—such as chronic pelvic pain, dysmenorrhea, dysuria, and infertility—it is increasingly recognized as a multifactorial disorder involving complex interactions between inflammatory, hormonal, angiogenic, oxidative stress-related, and cell survival-associated processes. Despite its high prevalence and substantial impact on quality of life, currently available therapeutic options remain limited in efficacy and are frequently associated with considerable adverse effects or high recurrence rates [ 1 , 2 ]. Current treatment strategies are primarily based on pharmacological and surgical interventions. First-line therapies include nonsteroidal anti-inflammatory drugs (NSAIDs), combined oral contraceptives, gonadotropin-releasing hormone (GnRH) analogs, and progestogens. Although these approaches may provide symptomatic relief, they are often associated with adverse effects such as gastrointestinal disturbances, hepatic and renal dysfunction, weight gain, vasomotor symptoms, and mood disorders. Furthermore, a considerable proportion of patients exhibit an inadequate response to treatment [ 3 , 4 , 5 ]. Surgical treatment remains an important therapeutic option, particularly in advanced cases or when pharmacological management fails. However, even well-executed surgical interventions do not guarantee long-term disease control. Recurrence rates remain high, reaching approximately 21.5%, while five-year recurrence rates range from 40% to 50%. These limitations underscore the urgent need for alternative or adjunctive therapeutic approaches that are both effective and associated with improved tolerability [ 6 , 7 , 8 ]. In recent years, increasing attention has been directed toward natural bioactive compounds as potential modulators of molecular pathways involved in endometriosis pathogenesis. Experimental studies suggest that these compounds may influence key processes involved in disease progression, including inflammatory signaling, angiogenesis, oxidative stress, apoptosis, and redox homeostasis [ 9 , 10 ]. Importantly, the therapeutic potential of natural bioactive compounds lies not only in their individual biological effects but also in their capacity to simultaneously modulate multiple molecular targets. Such pleiotropic activity may be particularly relevant in heterogeneous and multifactorial disorders such as endometriosis, in which numerous interconnected pathogenetic pathways contribute to lesion persistence and progression. Although the effects of natural compounds on individual mechanisms involved in endometriosis have been increasingly investigated, these findings are often presented within separate biological contexts. As a consequence, interactions between inflammatory, angiogenic, hormonal, and cell survival-related pathways remain less clearly integrated. A more comprehensive perspective may therefore help to better understand the potential role of natural bioactive compounds in the modulation of disease-related processes. Nevertheless, clinical evidence remains limited, and further studies are required to establish their efficacy, safety, and potential role in future therapeutic strategies [ 11 , 12 , 13 ]. The aim of this integrative review is to provide a comprehensive overview of the molecular mechanisms involved in endometriosis and to evaluate the therapeutic potential of natural bioactive compounds as modulators of interconnected pathogenetic pathways. Particular emphasis is placed on the relationships between inflammatory, angiogenic, hormonal, oxidative stress-related, and cell survival-associated processes, as well as on the ability of natural compounds to influence multiple targets simultaneously. By bringing together evidence from different biological levels, this review aims to provide a broader perspective on the potential role of natural bioactive compounds in the context of current therapeutic challenges and future treatment strategies for endometriosis [ 14 ].

Results

Natural bioactive compounds are increasingly being considered as potential modulators of endometriosis due to their ability to influence several molecular pathways involved in disease pathogenesis. Many of these compounds affect more than one biological process, including inflammation, oxidative stress, angiogenesis, hormonal signaling, and cell survival. As a result, their biological effects often extend beyond a single molecular target [ 49 , 50 , 51 , 52 ]. The multi-target activity of these compounds across key pathogenetic axes is summarized in Table 1 and Figure S1 showing the compound patterns has been added. Bioactive compounds display diverse activity profiles along the NF-κB–redox–inflammatory axis. Some compounds modulate several interconnected pathways, whereas others act primarily on specific components of inflammatory signaling. Polyphenols such as resveratrol, curcumin, and EGCG reduce oxidative stress while simultaneously attenuating NF-κB-mediated inflammatory responses. As a result, they influence several processes involved in lesion development and persistence [ 129 ]. Recent studies have further shown that curcumin suppresses STAT3- and JNK-dependent inflammatory signaling while reducing IL-6 and TNF-α expression. In addition, resveratrol attenuates inflammatory responses partly through SIRT1 activation [ 63 , 74 , 130 ]. Similar effects on oxidative stress and inflammatory signaling have also been reported for myricetin, carnosic acid, and luteolin. These findings further support the role of antioxidant compounds in regulating inflammatory pathways associated with endometriosis. Luteolin has also been shown to modulate NF-κB- and MAPK-dependent signaling pathways involved in the inflammatory response [ 103 , 105 , 127 , 130 ]. In contrast, compounds such as baicalein and nobiletin appear to exert more focused effects on selected inflammatory mediators and signaling pathways [ 112 , 131 ]. Overall, these findings indicate that natural bioactive compounds regulate inflammatory processes through diverse mechanisms. Their activity ranges from broad modulation of oxidative stress and NF-κB signaling to more selective effects on individual inflammatory mediators. Natural bioactive compounds exert anti-angiogenic effects by interfering with different stages of the HIF-1α–VEGF signaling cascade. Some compounds, including curcumin, EGCG, and ginsenosides, have been reported to modulate hypoxia-related pathways, including HIF-1α stabilization. Others, such as xanthohumol and nobiletin, primarily affect endothelial cell proliferation, migration, and vascular remodeling. Xanthohumol has also been reported to interfere with VEGF-related signaling and angiogenic responses [ 11 , 82 , 106 , 128 ]. This finding supports its potential role in regulating vascular processes associated with endometriosis. Recent evidence further indicates that curcumin suppresses VEGF expression and inhibits the migratory capacity of ectopic endometrial cells. These effects further support its anti-angiogenic activity [ 64 ]. Together, these observations highlight the close relationship between angiogenesis, inflammation, and hypoxia in endometriosis [ 16 , 64 , 81 , 132 ]. The modulation of estrogen signaling is one of the mechanisms through which bioactive compounds may influence endometriosis-related processes. These effects extend beyond direct receptor interaction and include regulation of aromatase activity and local steroidogenesis. Phytoestrogens such as genistein and daidzein can interact with estrogen receptors. In contrast, compounds such as quercetin and puerarin have been reported to affect pathways involved in estrogen biosynthesis [ 9 , 11 , 79 , 90 ]. Puerarin has also been shown to suppress aromatase expression and modulate ERα/ERβ- and ERK-dependent signaling, thereby reducing estrogen-dependent proliferation of ectopic endometrial cells [ 95 ]. Recent evidence further indicates that quercetin promotes decidualization and improves endometrial receptivity by modulating estrogen-responsive signaling pathways [ 76 ]. Oleuropein has also been associated with the regulation of estrogen-related pathways and apoptotic mechanisms, suggesting effects that extend beyond hormonal signaling alone [ 104 ]. However, the biological effects of phytoestrogens may vary depending on factors such as dose, receptor subtype, and the hormonal environment. Therefore, although these compounds show promising activity in experimental models, further clinical studies are needed to better define their therapeutic potential and safety in endometriosis. Given the close relationship between estrogen signaling and inflammatory activity, these findings further support the interconnected nature of the molecular mechanisms involved in endometriosis. Bioactive compounds may influence the invasive behavior of endometrial cells by modulating epithelial–mesenchymal transition (EMT) and related migratory processes. They regulate transcription factors involved in EMT and affect extracellular matrix remodeling and cell adhesion. Compounds such as resveratrol, naringenin, and isoliquiritigenin have been reported to attenuate EMT-related signaling and reduce cellular motility. Resveratrol also suppresses TGF-β- and MMP-9-dependent pathways involved in EMT and tissue invasion [ 73 ]. Because EMT is closely linked to inflammatory and proliferative pathways, its modulation may also influence lesion development and persistence [ 37 , 133 ]. Natural bioactive compounds have been reported to influence pathways involved in both cell survival and programmed cell death. These processes are frequently dysregulated in endometriosis. Compounds such as quercetin, luteolin, and chrysin have been shown to enhance apoptotic activity while reducing pro-survival signaling. Recent evidence further indicates that quercetin promotes apoptosis by modulating the AKT/ERK/p53 signaling axis [ 76 ]. These effects are associated with alterations in mitochondrial pathways, including changes in the Bax/Bcl-2 ratio and activation of caspase-dependent mechanisms [ 134 , 135 ]. The effects of these compounds extend beyond apoptosis and include the regulation of cellular proliferation and turnover. In addition, curcumin has recently been shown to suppress the H19/IGF signaling pathway, contributing to reduced proliferation of ectopic endometrial cells [ 64 ]. As a result, modulation of cell survival pathways may limit the persistence of ectopic endometrial cells [ 10 ]. The clinical relevance of these findings remains dependent on pharmacokinetic factors, including bioavailability, metabolism, and achievable tissue concentrations in vivo [ 136 ]. These translational aspects are summarized in Table 2 .

Conclusions

Endometriosis is a multifactorial disease in which inflammatory, angiogenic, hormonal, oxidative stress-related, and cell survival-associated processes remain closely interconnected. The interactions between these pathways contribute to lesion development, persistence, and progression. Natural bioactive compounds have emerged as potential modulators of several mechanisms involved in endometriosis pathogenesis. As discussed in this review, many of these compounds affect more than one molecular pathway, including inflammation, angiogenesis, estrogen signaling, epithelial–mesenchymal transition, oxidative stress, and apoptosis. This broad spectrum of activity may be particularly relevant in a disease characterized by complex interactions between multiple biological processes. Although most of the available evidence is derived from experimental studies, the findings summarized in this review support further investigation of natural bioactive compounds in endometriosis. Their clinical application will require further validation in well-designed human studies, together with improved strategies to enhance bioavailability and a better understanding of their mechanisms of action.

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