Exploring the therapeutic potential of disulfiram in endometriosis: mechanisms targeting inflammation, oxidative stress, pyroptosis, and angiogenesis

Disulfiram (DSF), as a member of the dithiocarbamate family, has been approved by the U.S. Food and Drug Administration (FDA) and has been safely used for the treatment of chronic alcoholism for over sixty years by inhibiting aldehyde dehydrogenase (ALDH) [ 46 , 47 ]. Clinical trials have shown that DSF is not only well-tolerated but also has minimal side effects. [ 47 , 48 ]. Recently, growing evidence suggests that DSF demonstrates therapeutic potential for a broad spectrum of conditions, including inflammation, cancer, metabolic disorders, and Lyme disease. [ 49 – 53 ]. Numerous mechanistic studies have shown that DSF has anti-inflammatory [ 49 ], anti-tumor [ 46 , 50 , 51 ], anti-obesity[ 53 ], anti-parasitic, and anti-hepatitis C virus infection effects [ 54 ]. Upon activation, M1-microglia upregulate the secretion of TNF-α. This pro-inflammatory cytokine can contribute to necrotic processes that ultimately compromise the integrity of the blood–brain barrier (BBB). [ 50 ]. After TBI, tight junction are reduced at the mRNA level [ 51 ]. C3q is one of the complementary initiation components involved in synaptic loss. Studies have found C1q to be upregulated in the hippocampus after TBI, concomitant with synaptic loss 30 days after injury. The markers of pyrolysis, such as caspase-1, were upregulated after TBI [ 52 ]. This indicated that infliximab has an effect of alleviating pyrolysis in addition to anti-inflammatory and anti-oxidant effects. Table 1 Effects of disulfiram on inflammation, oxidative stress, pyroptosis and pathogenesis Action DSF molecular target Biological/pharmacological effect References TLR Inhibits NF-κB signaling pathway expression [ 56 , 57 ] NF-κB/NLRP3 Suppresses NF-κB anf NLRP3 inflammasome activation [ 58 ] Inflammation NF-κB subunits Inhibits neclear translocation of NF-κB [ 59 ] Wnt and NF-κB pathways Modulates Wnt and NF-κB signaling [ 60 ] Nrf2/HO-1 Activates Nrf2/HO-1 pathway to ameliorate oxidative inflammation [ 66 ] ROS/NLRP3 Attenuates ROS production and NLRP3 inflammasome activation [ 61 ] Oxidative stress Mitochondrial-independent ROS Reduces mitochondrial-independent ROS generation [ 62 ] GSDMD Inhibits apoptosis by eliminating GSDMD pores [ 63 ] pyroptosis NLRP3 Suppresses pyroptotic cell death via NLRP3 inflammasome inhibition [ 58 , 65 ] Caspase-1 Inhibits Caspase-1-dependent pyroptosis in macrophages [ 64 ] VEG Inhibits vascular endothelial growth(VEGF) factor expression [ 66 ] Pathogenesis EGFR/c-Src/VEGF Downregulates EGFR/c-Src/VEGF signaling pathway [ 67 ] NF-κB Inhibits Pathogenesis by reducing [ 51 ] Effects of disulfiram on inflammation, oxidative stress, pyroptosis and pathogenesis

The clinical management of EMS faces several profound and interconnected challenges that underscore the critical need for novel therapeutic strategies. Current paradigms, primarily comprising surgical intervention and hormonal suppression, provide incomplete solutions for most patients. Surgical excision of endometriotic lesions remains the gold standard for symptom alleviation and fertility restoration. However, its efficacy is markedly limited by high recurrence rates, which range from 20 to 50% within five years post-operation, highlighting its inability to alter the fundamental disease process. Pharmacological management, predominantly involving hormonal therapies such as oral contraceptives, gonadotropin-releasing hormone (GnRH) agonists, and progestins, aims to induce estrogen suppression or a pseudo-menopausal state. While often providing symptomatic relief, these approaches are fundamentally palliative, fail to target the core inflammatory, oxidative, and angiogenic mechanisms of EMS, and are frequently associated with intolerable side effects that preclude long-term use. These adverse effects, including loss of bone mineral density, vasomotor symptoms, and metabolic changes, significantly diminish patient quality of life and treatment adherence [ 1 , 10 ]. Compounding these therapeutic limitations are profound diagnostic challenges. The requirement for surgical confirmation invariably leads to a protracted delay from symptom onset to definitive diagnosis, often spanning several years. This diagnostic lag is further exacerbated by the absence of reliable non-invasive biomarkers and the remarkable heterogeneity in disease presentation and patient symptoms. Consequently, the window for early intervention is often missed, allowing for disease progression [ 11 – 13 ]. It is within this context of limited efficacy, high recurrence, treatment-limiting side effects, and diagnostic delays that the investigation of disulfiram (DSF) is positioned. Unlike current hormonal therapies, DSF presents a multi-targeted mechanism of action capable of simultaneously addressing key pathological pathways, including inflammation, oxidative stress, pyroptosis, and angiogenesis, that are neglected by existing standards of care. Therefore, DSF represents a promising path toward a disease-modifying therapy that could potentially reduce recurrence rates and offer a more sustainable and mechanistic treatment option for patients. Notably, the core pathological drivers of EMS—inflammation, oxidative stress, pyroptosis, and angiogenesis—are not sequential but operate within a self-reinforcing network. Chronic inflammation generates oxidative stress, which in turn can activate the NLRP3 inflammasome to induce pyroptosis. This inflammatory cell death releases potent cytokines (e.g., IL-1β) that further fuel inflammation and stimulate angiogenic factors, such as VEGF. This vicious cycle underscores the inherent limitation of single-pathway therapies and provides a compelling rationale for investigating a pleiotropic agent, such as DSF, which is pharmacologically equipped to disrupt this network at multiple synergistic nodes.

The role of DSF in EMS. DSF inhibits the NF-κB signaling pathway by inhibiting TLR4. DSF can also directly downregulate the NF-κB signaling pathway, thereby further inhibiting the release of inflammatory cytokines TNF-α, IL-6 and IL-1β As outlined in Sect.  3.1 , the NF-κB signaling pathway is a central driver of inflammation and cell proliferation in EMS. DSF exerts its anti-inflammatory effects by targeting this pathway at multiple levels. First, it inhibits Toll-like receptor 4 (TLR4), an upstream activator of NF-κB [ 59 , 60 ]. Second, acting as a novel proteasome inhibitor, DSF directly interferes with the NF-κB activation cascade, preventing the nuclear translocation of NF-κB and the subsequent transcription of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β [ 61 ]. This dual inhibition effectively dampens the chronic inflammatory response, as evidenced by a study showing DSF prevents ectopic lesion growth in part through NF-κB suppression [ 62 ]. By suppressing the NF-κB-driven inflammatory cascade, DSF reduces a primary source of ROS, thereby mitigating the oxidative stress component of EMS. OS is associated with EMS pathophysiology [ 63 ]. Recent studies have shown high levels of ROS in ectopic endometrial cells. Additionally, OS can promote endometrial cell proliferation and cause damage [ 64 ]. Some studies have also found that a decrease in endogenous antioxidant enzyme activity and an increase in ROS have been detected in patients with EMS. It has been shown that DSF inhibits OS while also inhibiting the activation of the NLRP3 inflammasome [ 65 ]. Evidence indicates that DSF reduces intracellular ROS production by suppressing NADPH oxidase activity. It also directly inhibits NLRP3-dependent IL-1β secretion. Given that ROS is a known activator of the NLRP3 inflammasome, these findings suggest that DSF mitigates NLRP3 activity, at least in part, through ROS scavenging. Glycogen synthase kinase-3β (GSK-3β) suppresses nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant response. Inhibition of Nrf2 exacerbates oxidative stress, which in turn promotes NLRP3 inflammasome activation. This vicious cycle contributes to chronic inflammation and oxidative damage in EMS. Furthermore, DSF suppresses oxidative damage-related pyroptosis and inflammation via modulation of the GSK-3β/Nrf2/NLRP3 pathway [ 66 ]. Therefore, DSF may improve EMS by inhibiting the oxidative stress. The inhibition of the NLRP3 inflammasome by DSF, as described here, directly translates to the suppression of pyroptosis, blocking this highly inflammatory cell death pathway. Fig. 5 PRISMA flow diagram of the literature search and selection process PRISMA flow diagram of the literature search and selection process GSDMD, as a member of the Gasdermin family proteins, is the sole and final executor of pyroptosis in the process. After GSDMD-activated caspase-1/4/5/11 cleaves the N- and C-terminus, the N-terminal fragments can be transferred to the plasma membrane and form membrane pores, thereby inducing the occurrence of pyroptosis [ 67 ]. Among them, Cys191 is important for GSDMD pore formation in cells. Recently, DSF has been shown to act as a potent inhibitor of GSDMD pore formation, which can inhibit pyroptosis by covalently modifying reactive Cys residues, especially Cys191, thereby eliminating GSDMD pore formation. In addition, DSF can reduce the release of inflammatory mediators such as TNF and IL-6 through the GSDMD pathway, further reducing the inflammatory response to some extent [ 51 ]. Among the inflammasome complexes, the NLRP3 inflammasome is the most characteristic, and it is a key node in regulating the maturation of two pro-inflammatory interleukin (IL)-1 family cytokines, IL-1β and IL-18, as well as the activation of caspase-1. Experimental studies have shown that DSF additionally inhibits pyroptosis by inhibiting the NLRP3 inflammasome, thereby further inhibiting the release of inflammatory cytokines IL-1β and IL-18 [ 68 ]. Pyroptosis-related factors such as NLRP3, caspase-1, IL-1β, and IL-18 are elevated in ectopic endometrium. Therefore, DSF may improve EMS by inhibiting the pyroptosis. The reduction in pyroptosis-derived IL-1β concurrently diminishes a key stimulus for VEGF expression, contributing to the anti-angiogenic effects outlined next Table 1 . Angiogenesis is one of the key factors contributing to the survival and development of ectopic endometrial implants in EMS. In EMS, both angiogrowth factor and TNF-α promote ectopic lesion growth. Additionally, the EGFR/Src pathway is activated in endometriotic cells and stimulates VEGF expression and signaling, promoting angiogenesis and lesion vascularization. [ 43 , 61 ]. DSF exerts a dual inhibitory effect on TNF-α production and VEGF release (in a dose-dependent manner). This dual inhibition results in reduced angiogenesis and inflammation. Another study has shown that DSF can inhibit EGFR activation and Src kinase activity, thereby disrupting downstream VEGF expression by modulating the EGFR/Src/VEGF pathway, which can be enhanced by combination with Cu. [ 62 ]. In addition, one study suggests that DSF can inhibit angiogenesis with zn as a chelator. The NF-κB pathway activates VEGF, which stimulates cell proliferation and angiogenesis in EMS. Moreover, DSF further inhibits angiogenesis by inhibiting the NF-κB pathway [ 68 ]. Therefore, DSF may improve EMS by inhibiting the angiogenesis (Fig.  5 ).

EMS is a chronic inflammatory condition characterized by the central roles of inflammation, oxidative stress, pyroptosis, and angiogenesis in its pathogenesis, as extensively discussed in this report. In light of the significant limitations of current therapeutic strategies, including high recurrence rates post-surgery, the palliative nature and systemic side effects of hormonal interventions, and the absence of disease-modifying agents, there is an urgent need for novel treatments that target the multifaceted mechanisms of EMS. DSF, an agent with pleiotropic biological activities, has emerged as a promising therapeutic candidate to address these clinical challenges. Its potential utility is underpinned by its ability to simultaneously modulate several core pathological processes: First, DSF potently suppresses inflammation, a cornerstone of EMS progression. Through inhibition of the NF-κB signaling pathway and subsequent downregulation of pro-inflammatory cytokine production, DSF attenuates the chronic inflammatory milieu, thereby limiting disease advancement. Second, DSF mitigates oxidative stress, a key contributor to lesion development and persistence. By enhancing antioxidant enzyme activity and scavenging reactive oxygen species (ROS), DSF reestablishes redox homeostasis, reducing oxidative damage and supporting cellular repair. Third, DSF effectively inhibits pyroptosis, a highly inflammatory form of programmed cell death. Through targeting pivotal components of the inflammasome pathway, DSF curtails the release of interleukin-1β and other cytokines, thereby preserving tissue architecture and impeding lesion progression. Lastly, DSF exerts robust anti-angiogenic effects by interfering with VEGF-mediated signaling. This inhibition disrupts the formation of new microvasculature that sustains ectopic endometrial implants, effectively starving lesions of necessary nutritional support. Notwithstanding this promising mechanistic profile, translating DSF into clinical practice faces several translational barriers. These include the need to optimize its bioavailability, determine dosing regimens specific to EMS, and validate its efficacy in robust preclinical models that more accurately recapitulate human disease heterogeneity. Furthermore, well-designed clinical trials are essential to rigorously assess their safety, efficacy, and long-term tolerance in the EMS patient population. Notwithstanding this promising mechanistic profile, translating DSF into clinical practice for EMS faces specific translational and pharmacological challenges. First, inherent to DSF itself are considerations of its pharmacokinetics and safety profile in a new patient population. Its rapid metabolism may require innovative dosing regimens or delivery systems to maintain effective concentrations at endometrial lesions. Although historically safe for alcoholism, its long-term tolerability and specific side effects (e.g., potential neurological or dermatological reactions) in young women with EMS need dedicated study. Second, beyond the drug's properties, there is a need to optimize bioavailability, determine EMS-specific dosing regimens, and validate efficacy in robust preclinical models that more accurately recapitulate human disease heterogeneity. Furthermore, well-designed clinical trials are essential to rigorously assess its safety, efficacy, and long-term tolerance in the EMS patient population. In conclusion, DSF represents a compelling multi-target strategy to overcome the limitations of current EMS therapies. By concurrently addressing inflammation, oxidative stress, pyroptosis, and angiogenesis, it holds potential as a disease-modifying treatment. Future research should prioritize overcoming these translational hurdles to fully exploit its therapeutic potential.

Endometriosis (EMS) is a chronic inflammatory gynecological disorder characterized by the presence of endometrioid tissue outside the uterine cavity, primarily in the pelvic peritoneum, ovaries, and rectovaginal septum, and less frequently in the diaphragm, pleura, and pericardium. Traditionally defined as an estrogen-dependent condition, EMS affects approximately 5–10% of women of reproductive age worldwide, with a significantly higher prevalence of up to 50% among women experiencing infertility. Beyond its clinical manifestations, EMS imposes a substantial economic burden and severely impacts patients' quality of life [ 1 , 2 ]. In the United States alone, the estimated economic burden exceeds $22 billion annually [ 3 ]. Common clinical symptoms include pelvic pain, dysmenorrhea, nonmenstrual pelvic pain, and infertility. However, the variability in symptom severity and presentation often leads to diagnostic delays, with an average of 7–10 years from symptom onset to diagnosis [ 4 – 6 ]. EMS is categorized into distinct subtypes based on lesion location: superficial peritoneal endometriosis, ovarian endometriomas, and deeply infiltrating endometriosis (DIE). Each subtype exhibits unique pathophysiological features, clinical implications, and treatment responses. Despite growing awareness and research efforts, EMS remains underdiagnosed and inadequately managed, further compounding its adverse effects on patients and healthcare systems [ 1 , 7 ]. Pathophysiologically, EMS is driven by a complex interplay of factors, including retrograde menstruation, peritoneal immune dysfunction, angiogenesis, and molecular abnormalities in ectopic endometrial tissue. Emerging evidence further underscores the contributions of oxidative stress, epigenetic modifications, and microbiome dysregulation. However, significant knowledge gaps persist. A critical unanswered question is why only a subset of individuals experiencing retrograde menstruation develop EMS, suggesting a crucial role for undiscovered genetic susceptibilities and environmental triggers. Furthermore, the precise hierarchical relationship and crosstalk between these pathways—particularly how immune dysregulation, oxidative stress, and epigenetic modifications converge to promote lesion survival and pain sensitization—remain poorly defined. The field also lacks reliable biomarkers for early detection and disease stratification. Bridging these gaps requires a multi-faceted research approach. Future directions should prioritize integrated multi-omics studies to identify novel therapeutic targets, the development of more sophisticated animal models that recapitulate the human disease phenotype, and longitudinal clinical studies to validate the prognostic value of emerging biomarkers and to assess the efficacy of mechanism-based therapies, such as agents targeting NLRP3 inflammasome or Nrf2 pathways. This expanded understanding is essential to pave the way for novel, targeted, and personalized therapeutic strategies that move beyond symptomatic control to modify the underlying disease process [ 8 , 9 ].

There are many inflammatory cells within the endometriotic lesion. Among them, macrophages secreted and released IL-1β, IL-37, IL-6, and TNF- α. Mast cells (MC) release IL-2, IL-3, IL-6, IL-7, IL-7, IL-9, IL-10, IL-25, and nerve growth factor (NGF). Neutrophils release IL-8, IL-17, and IL-17. The cytokines and inflammatory mediators released by these inflammatory cells can, in turn, act on inflammatory cells to further increase inflammatory cell aggregation Normal menstruation is inherently an inflammatory process, marked by an increased presence of tissue-residing immune cells and inflammatory mediators. This process involves intricate interactions between resident immune cells and uterine stromal cells. These interactions regulate the synthesis and release of pro-inflammatory cytokines, chemokines, and prostaglandins (PGs), ultimately leading to localized vasoconstriction [ 14 , 15 ]. The most widely accepted theory for the development of EMS is retrograde menstruation, which refers to the backward flow of endometrial fragments through the fallopian tubes during menstruation, followed by their implantation onto the peritoneum or other organs within the peritoneal cavity [ 16 , 17 ]. However, it is important to note that while retrograde menstruation occurs in up to 90% of women, only 6–10% of menstruating individuals develop EMS [ 1 , 2 , 18 ]. This discrepancy suggests that additional factors play a critical role in the establishment and survival of ectopic endometrial implants. Recent studies have revealed that EMS lesions and peritoneal fluid in affected patients contain a high concentration of inflammatory cells, cytokines, and chemokines, creating a distinct inflammatory microenvironment [ 16 , 19 ]. During retrograde menstruation, inflammatory cells are recruited to the newly formed ectopic endometrial lesions, further amplifying the inflammatory response [ 14 , 20 , 21 ]. Key immune cells such as macrophages, mast cells, and neutrophils are prominently involved, driving the production of numerous inflammatory factors [ 22 – 24 ]. For instance, macrophages secrete and promote the release of interleukins, including IL-1β, IL-37, and IL-6, as well as tumor necrosis factor-α (TNF-α) [ 18 , 22 , 23 , 25 ]. Mast cells contribute to the inflammatory milieu by releasing IL-2, IL-3, IL-6, IL-7, IL-9, IL-10, IL-25, and nerve growth factor (NGF) [ 24 ]. Similarly, neutrophils release IL-8, IL-17, and IL-17α, further exacerbating the inflammatory cascade [ 25 , 26 ]. These cytokines and inflammatory mediators, in turn, act on immune cells, creating a feedback loop that amplifies the recruitment and activation of inflammatory cells [ 14 ]. The transcription factor nuclear factor-kappa B (NF-κB) is a master regulator of this sustained inflammatory response. In endometriotic lesions, NF-κB is constitutively active, driving the expression of key pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β) and promoting cell survival and proliferation, thereby cementing the chronic inflammatory microenvironment [ 55 – 58 ]. While inflammation is typically a protective, adaptive response to harmful stimuli, its dysregulation in EMS contributes to the pathological progression of the disease. However, when this protective mechanism is dysregulated, the inflammatory response can become excessive, which can have harmful effects on the body [ 27 ]. As mentioned above, this vicious cycle further enhances the growth and infiltration of EMS lesions and induces a chronic inflammatory microenvironment that can develop into chronic inflammatory diseases [ 14 ]. This sustained inflammatory milieu, characterized by activated macrophages and neutrophils, is a major source of reactive oxygen species (ROS), thereby creating a state of oxidative stress that exacerbates tissue damage. ROS are increased in EMS lesions, while endogenous antioxidant enzyme activity is decreased. Excessive release of ROS not only induces cell damage but also alters cellular function by destroying protein, lipid, and DNA structures. ROS can also promote the expression of the NF-κB signaling pathway, thereby promoting the occurrence of inflammation Oxidative stress (OS) is characterized by an imbalance between the production of ROS and the body's antioxidant defenses [ 28 , 29 ]. ROS, which are byproducts of normal oxygen metabolism, serve as inflammatory mediators that regulate cell proliferation but can also exert harmful effects when present in excess. Under physiological conditions, the human body maintains a delicate equilibrium between ROS and antioxidants. However, this balance is disrupted when ROS levels rise or antioxidant mechanisms are compromised, leading to oxidative stress. While moderate amounts of ROS are essential for normal cellular functions, excessive ROS production can overwhelm the body's natural antioxidant systems, creating an environment detrimental to normal female physiological processes [ 30 , 31 ]. In such conditions, the female reproductive system becomes particularly vulnerable to the damaging effects of ROS. Excessive ROS not only induces cellular damage, but also disrupts cellular function by degrading proteins, lipids, and DNA structures [ 32 , 33 ]. These alterations contribute to the development of various reproductive disorders, including endometriosis, polycystic ovary syndrome (PCOS), and unexplained infertility. Recent studies have demonstrated that patients with endometriosis exhibit decreased activity of endogenous antioxidant enzymes and elevated levels of ROS [ 34 ]. Furthermore, ROS can exacerbate endometriosis by promoting cell proliferation, angiogenesis, and inflammation through the activation of the NF-κB signaling pathway in peritoneal macrophages [ 35 ]. Furthermore, ROS serve as potent activators of the NLRP3 inflammasome, a key molecular platform that bridges oxidative stress to the induction of pyroptosis. Classical pyroptosis pathway in EMS. PAMPs and DAMPs induce inflammasome activation, particularly NLRP3, leading to subsequent caspase-1 activation. GSDMD is cleaved by activated caspase-1, resulting in an active GSDMD-N-terminal domain. The GSDMD-N-terminal domain forms membrane pores in the cell membrane and promotes the release of inflammatory mediators such as IL-1β and IL-18. The pro-inflammatory microenvironment produced in EMS favorably promotes the migration and fibrosis of EMS cells Pyroptosis is an inflammatory form of programmed cell death, which is mediated by Gasdermin family proteins [ 36 , 37 ]. Pyroptosis is an important defense mechanism in the immune system that clears pathogen-infected cells and triggers an inflammatory response [ 36 ]. Inflammasomes are protein complexes composed of multiple cytokines and inflammation-associated receptors, including inflammatory NLR family pyrin domain-containing 3 (NLRP3) that can be activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to recruit and activate and caspase-1. GasderminD (GSDMD) is a key executive protein in pyroptosis. GSDMD is cleaved by activated caspase-1 to produce an active GSDMD-N-terminal domain. The translocation of the GSDMD-N-terminal domain into the cell membrane forms a membrane pore, resulting in the release of cell contents and cell rupture [ 36 – 38 ]. GSDMD pores can cause the intracellular ion gradient to collapse and water to rush into the cell, eventually causing the cell to swell and rupture. GSDMD pores can also release large amounts of pro-inflammatory factors, such as IL-1β and IL-18, which trigger an inflammatory response [ 36 ]. However, pyroptosis, once overactivated, can cause inflammatory and autoimmune diseases, such as EMS and gestational diabetes, as well as obstetric and gynecological disorders [ 39 ]. In previous studies, the expression levels of pyroptosis-related proteins, such as NLRP3, caspase-1, IL-1β, and IL-18, in ectopic endometrium are significantly higher than those in normal endometrium [ 40 ]. The execution of pyroptosis results in the release of mature IL-1β and IL-18, which are powerful inducers of vascular endothelial growth factor (VEGF), thereby establishing a direct pro-angiogenic signal essential for lesion vascularization and growth. Angiogenesis is defined as the creation of new vascular branches from the extension of pre-existing blood vessels. This is a multi-step process that includes the breakdown of blood vessels, the degradation of the vascular basement membrane and the surrounding extracellular matrix (ECM), as well as the migration of endothelial and the formation of new blood vessels [ 41 ]. This process is first initiated by VEGF, which activates resting endothelial cells in the microvascular system to release matrix metalloproteinase (MMP). They mediate the degradation of the vascular basement membrane and further allow endothelial cells to migrate into surrounding tissues. In addition, the tubular branches of endothelial cells form vascular loops and novel basement membranes, which ultimately lead to the formation of new blood vessels [ 42 ]. Among them, VEGF is the most significant angiogenesis factor, which attaches to the vascular endothelium to induce angiogenesis and cell proliferation in the endothelium, as well as increased vascular permeability [ 43 ]. Angiogenesis is key to normal physiological processes and plays an important role in the normal menstrual cycle [ 44 ]. However, the reason why angiogenesis also plays a key role in the progression of EMS is because EMS is highly dependent on the formation of new vascular systems. At the same time, inflammation and oxidative stress promote the neovascularization of ectopic endometrial vessels and the establishment of microvascular networks. Angiogenesis has been reported to be a major feature of EMS, but the underlying mechanism of angiogenesis in the disease remains unknown [ 45 ]. Thus, angiogenesis in EMS is not an independent event but is critically supported and stimulated by the preceding inflammatory, oxidative, and pyroptotic milieu.