The relationship between inflammation and neurogenesis has been studied to some degree in other chronic pain conditions (7–10), but has not been well researched in endometriosis. Dysregulated immune system is believed to be a key driver of endometriosis contributing to inadequate removal of endometrium fragments from peritoneal cavity. This further stimulates local inflammation. Endometrial lesions contain increased amounts of activated peritoneal mast cells and macrophages and have a lowered cytotoxicity of T and NK cells (11–14). Higher levels of inflammatory mediators such as tumor necrosis factor α (TNFα), interleukins, prostaglandin E2 (PGE2), nerve growth factor (NGF) and chemokine RANTES/CCL5 were found in lesions and perioneal fluid of endometriosis patients (15, 16). It is likely that those factors also stimulate sensory nerve endings. Pelvic innervation was shown to differ in endometriosis sufferers compared to healthy controls. The presence of endometriosis-associated nerve fibers was correlated with pain perception in women affected by the condition (17). In those experiencing pelvic pain, the distance between endometrial glands and the nerve supply was found to be shorter (18). Additionally, nerve fiber densities were significantly higher in women with endometriosis compared to controls (19, 20). A greater number of nerve fibers were also identified in peritoneal endometriotic lesions than in normal peritoneum (21). Notably, subtypes of deep infiltrating endometriosis exhibited an even denser nerve supply compared to the innervation of the peritoneum (21).

It is possible that sensory nerves within endometriotic lesions interact with peritoneal immune cells by secreting neurotrophic factors. In peritoneal lesions, an increased number of macrophages have been observed to colocalize with nerve fibers (22), a process found to be driven by estradiol (23). Elevated immunoreactivity of NGF has also been reported near endometriotic glands (21). A recent study demonstrated that endometriosis-related pain is mediated through NGF-TrkA signaling (24). Furthermore, the estrogen-driven interplay between neurogenesis and the immune system has been shown to correlate with dysmenorrhea in endometriosis (25). The schematic of a cross-talk between inflammation and neurogenesis in endometriosis is presented in Figure 1 .

The brain, serving as the central coordination hub for all environmental stimuli, undergoes physiological transformations under their influence. Novel and intense stimuli activate neurons to restructure synaptic connections and form new ones, thereby initiating neurogenesis. Pain represents an exceptionally potent stimulus that induces significant modifications in the brain regions responsible for its processing. These changes are accompanied by observable electrophysiological alterations. In a study by Duric et al. (26) it was successfully demonstrated that pain can alter hippocampal morphology and gene expression in a mouse model of chronic and acute pain. Bromodeoxyuridine staining indicated that neurogenesis in the hippocampal dentate gyrus was significantly reduced after long-term inflammatory nociception, implicating that prolonged nociceptive input triggers maladaptive neural plasticity, including the remodeling of synaptic connections and disruption of neurogenic processes. These findings suggest that neural changes induced by chronic pain, such as impaired neurogenesis and maladaptive plasticity, may play a significant pathophysiological role in endometriosis-associated pain.

Mice carrying endometriosis exhibited a higher sensitivity to pain, and showed signs of depression and anxiety. Their insula, amygdala, hippocampus and cerebral cortex all showed differential gene expression compared to non-endometriosis controls (27). The central nucleus of the amygdala, a region critically involved in pain perception and emotional processing, revealed significant alterations in gene expression and intrinsic electrophysiological properties of neurons in murine model of endometriosis (5). Others have reported an increased microglial soma size in the cortex, hippocampus, thalamus, and hypothalamus of mice with endometriosis (28). Together, these observations underscore the contribution of central nervous system changes—such as neural remodeling, neuroinflammation, and sensitization processes—to the development and maintenance of chronic pain in endometriosis.

Women with endometriosis exhibit distinct neurobiological patterns compared to other patients with chronic pelvic pain. They show increased gray matter volume in the cerebellum (29). In addition, compared to pain-free controls, women with endometriosis demonstrate enhanced connectivity between the anterior insula and the medial prefrontal cortex, two regions heavily involved in pain perception and processing. Furthermore, proton magnetic resonance spectroscopy revealed altered brain chemistry in these patients, with higher concentrations of combined glutamine and glutamate in the anterior insula (30). Adaptations in the brain in response to chronic pain are presented in Figure 2 .

Dorsal root ganglion (DRG) neurons play a central role in mediating chronic pain associated with endometriosis. Acting as key relays between peripheral tissues and the central nervous system, DRG neurons undergo significant structural and molecular changes, driven by neurotrophic factors, such as NGF and brain-derived neurotrophic factor (BDNF). These factors have been documented in both human tissue samples and rodent models of endometriosis (31, 32) and they were found to promote excessive axonal sprouting and hyperinnervation of endometriotic lesions, amplifying nociceptive input to the spinal cord (33) ( Figure 1A ). Additionally, BDNF and calcitonin gene-related peptide (CGRP) contribute to pain amplification by enhancing neuronal excitability and fostering neuroimmune interactions within the DRG (31, 34).

Recent research has highlighted the molecular mechanisms underlying DRG neuron hyperexcitability in endometriosis, with a focus on ion channel regulation (see Figure 1B ). Transient receptor potential (TRP) channels, particularly TRPV1 and TRPA1, have emerged as key mediators of nociception in sensory neurons. Elevated expression of TRPV1 and TRPA1 has been observed in both human and rodent DRG neurons, correlating with heightened pain sensitivity and estrogen regulation (35–37). The pharmacological blockade of TRPV1 has demonstrated effectiveness in reducing pain responses in animal models, reinforcing its role in peripheral sensitization (35). In addition to TRP channels, sodium channels, such as NaV1.7, are significantly upregulated in neurons innervating pelvic organs affected by endometriosis. Functional studies have shown that NaV1.7 activation increases nociceptive sensitivity, further contributing to pain amplification (38). Purinergic signaling via the P2X3 receptor is another critical mechanism in pain modulation. Upregulation of P2X3 in DRG neurons has been linked to activation of the ATF3/AP-1 and ERK signaling pathways in animal models of endometriosis, establishing its role as a driver of nociceptive signaling (39–41). These findings underscore the central role of ion channel upregulation in DRG neuron hyperexcitability and its contribution to pain sensitization in endometriosis. Emerging therapeutic strategies have targeted these pathways. Experimental models have shown that CGRP-RAMP1 inhibition reduces endometriotic lesion size and pain responses, in mice suggesting clinical applications for modulating DRG-mediated nociceptive signaling (42). Moreover, research into DRG neuromodulation highlights its potential as a promising strategy for treating chronic pain, given the unique physiology and accessibility of DRG neurons (35–37). These findings underscore the interconnected role of neuroimmune and inflammatory signaling in peripheral sensitization and chronic pain management.

Endometriosis is characterized by the aberrant presence of pathological neurons within affected tissues (43) ( Figure 1C ). NGF and neurotrophin-3 (NT-3), are expressed in peritoneal endometriotic implants and in the peritoneal fluid of patients with endometriosis (44). NGF plays role in inflammation and pain processing: inflammatory cells stimulate the release of neuroactive cytokines and inflammatory mediators, with IL-1β and TNF-α acting as potent triggers for NGF synthesis (45) (see Figure 1A ). Advances in immunohistochemistry have facilitated the detailed analysis of neuronal marker distribution in endometrial tissue, the myometrium, and endometriotic lesions, enabling a more precise understanding of the neural components involved in the disease pathology. In their research, Al-Jefout et al. (46) reported that the distance between endometrial glands and nerve fibers in endometriotic lesions was significantly shortened in women experiencing pain compared to those without pain (assessed with pain score). Additionally, women with endometriosis and pain symptoms exhibited a significantly higher density of nerve fibers than women with endometriosis- related infertility but no pain (46). Arnold et al. (47) identified an imbalance between sympathetic and sensory nerve fibers in peritoneal endometriosis. The peritoneal fluid of patients with endometriosis, compared to that from women without the disease, was shown to induce increased sprouting of sensory neurites from dorsal root ganglia while simultaneously inhibiting neurite outgrowth from sympathetic ganglia. Sensory C and autonomic nerve fibers were observed in the functional layer of the endometrium exclusively in women with endometriosis, with even greater densities detected in the basal layer, which implicates the possible role in maintenance of inflammation and pain (47). Tokushige et al. (19) further described the presence of numerous small unmyelinated nerve fibers in the functional layer of the endometrium in patients with endometriosis. These nerve fibers were predominantly located in the deeper portion of the functional layer, though some were observed in close proximity to the endometrial epithelial surface, particularly near blood vessels and glands. In contrast, no nerve fibers were detected in the functional layer of the endometrium in patients without endometriosis (21). Interestingly, the density of nerve fibers was greater during the secretory than in the menstrual or proliferative phases of the endometrial cycle (21).

Mast cells play a key role in neuromodulation by mediating a crosstalk between immune and nervous system (48, 49). They release a range of biomediators that impact neuroinflammation and pain signaling. The proliferation and homeostasis of mast cells is dependent on JAK/STAT pathway (50). The primary physiologic function of mast cells is to facilitate immune responses to infectious agents (51) but they are also involved in the degradation of toxic endogenous peptides (52) and wound healing responses (53–55). Overactivated mast cells are best known for promoting chronic inflammatory disorders and are early effectors of allergic disease, urticaria, anaphylaxis, arthritis, and asthma (56, 57). Their dysfunction can lead to mast cell activation syndrome and they have been shown to contribute to ulcerative colitis, Crohn’s disease and multiple sclerosis among others (58, 59). Mast cells can cause profound inflammation and vasodilation and release inflammatory mediators including histamines, cytokines (TNF, IL-1, IL-6, IL-8), tryptase, chymase, prostaglandins and growth factors (60, 61).

Mast cells are crucial in the development of protective pain and they are thought to contribute to the regulation of pain signaling (62, 63). The role of mast cells has been correlated with the development of chronic pain in various conditions including rheumatoid arthritis, irritable bowel syndrome, interstitial cystitis, chronic pelvic pain syndrome and chronic prostatitis and in several brain disorders (63, 64). Activated mast cells are likely to sensitize primary nociceptive neurons by the release of histamines, NGF and pro-inflammatory cytokines TNF and IL-8; the latter has been shown to activate prostaglandin-independent hyperalgesia in vivo (65).

Mast cells are speculated to play a key role in endometriosis; they impact the recruitment and performance of other immune cells. Increased levels of mast cells and their augmented degranulation was shown in endometrial tissue of animal models and humans (66–68) ( Figures 1D, E ). We have shown that endometrial lesion tissue has an increased expression of mast cell markers including KIT, CPA3 and both MS4A2 and MS4A6A compared to control endometrium (69). Mast cells were found to promote endometrial cells migration in in vitro assays (70) and shown to colocalize to the vasculature of ovarian endometriomas. Endometrial lesions secrete mediators such as nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and substance P, which are known to attract mast cells. Studies have shown that increased mast cell infiltration and degranulation are influenced by NGF production within endometrial tissue (33). Mast cells are believed to partake in neuropathic pain development in endometriosis. Pain intensity in patients correlated positively with an elevated number of mast cells in lesions, which were mostly located near nerve fibers (71).

Human MrgprX2 and its murine ortholog MrgprB2 are G protein–coupled receptors selectively expressed on connective-tissue mast cells. These receptors mediate rapid, non-IgE-dependent mast cell activation in response to neuropeptides such as substance P and PACAP, as well as various drugs and cationic peptides. Their activation establishes a bidirectional communication axis between mast cells and peripheral sensory neurons, promoting neurogenic inflammation and pain (72, 73).

In vivo studies across multiple tissues-including skin, meninges, bladder, and gut-have demonstrated the functional importance of this pathway. In murine models of interstitial cystitis/bladder pain syndrome (IC/BPS), MrgprB2-dependent mast cell–neuron circuits promote bladder inflammation and colonic hypersensitivity; MRGPRX2 antagonism reduces these effects in humanized mice (74). Similarly, in migraine models, MrgprB2+ meningeal mast cells respond to compound 48/80 or PACAP with pain behaviors absent in knockout animals; MRGPRX2+ humanized mice show enhanced responses (72). In the skin, MrgprB2 mediates mast cell degranulation and neurogenic inflammation induced by substance P, LL-37, and drugs like compound 48/80, with effects abolished by receptor knockout or antagonism (73). In the gut, human colonic mast cells express MRGPRX2 and respond to agonists, with altered profiles in IBS biopsies (75).

Despite this broad relevance, MrgprX2/B2 signaling has not been studied in gynecological tissues to-date. The presence of MrgprB2+ mast cells was shown in the uterus and mammary gland (76), yet no in vivo data addresses receptor activation, neuron interaction, or its roles in pain or lesion formation.

This gap limits our understanding of mast cell–neuron signaling in reproductive disorders. Future studies could reveal whether MrgprX2/B2 contributes to pelvic pain and inflammation in conditions like endometriosis offering new targets for non-hormonal therapy.

Both neurogenesis and inflammation converge on JAK/STAT pathway, which provides a rapid membrane-to-nucleus signaling platform that mediates cellular inflammation response (77, 78). This central pathway is responsible for transmitting extracellular signals that govern migratory and invasive properties of cells. JAK/STAT pathway overactivation was shown to facilitate proliferation and angiogenesis in cancer (79), in breast malignancies its prolonged activation was linked with tumor development (80) and therapy resistance (81).

Various cytokines that play a role in the development of inflammatory and autoimmune diseases utilize JAKs and STATs proteins to transmit intracellular signals and impact homeostasis. Dysregulation of JAK/STAT pathway and mutations and polymorphisms in its genes correlate with numerous immunodeficiency syndromes (82, 83). Altered JAK/STAT signaling was detected in endometriosis (84) ( Figure 1F ). Phosphorylation of STAT3 was upregulated in endometriosis lesions (85) and activated STAT3 increased proliferation of endometrial stromal cells (86). IL-6 mediated activation of STAT3 was correlated with fibrosis in endometriosis (87).

The JAK/STAT pathway plays an essential role in maintenance of neural stem cells (NSCs) (88, 89) and pain signaling (90). On the other hand, cytokine IL-15 produced by adult NSCs contributes to STAT proteins activation (91). STAT3 has been shown to regulate neuropathic pain maintenance in rats. Pain resulting from nerve injury was accompanied by an increase in STAT3 phosphorylation in microglial cells of dorsal spinal cord (92) and by an increase in JAK/STAT signaling and resulting augmented proliferation of astrocytes (93). IL-6 signaling system is known to activate JAK/STAT pathway; increased expression of IL-6 mRNA was observed in dorsal root ganglia and in dorsal spinal cord of rats with neuropathic pain (92). JAK/STAT pathway was shown to be involved in synaptic plasticity in the brain (94).

Gain-of-function mutations in the JAK–STAT signaling pathway are well-established molecular drivers of immune dysregulation (95–98). Such mutations typically enhance cytokine responsiveness or lead to constitutive activation of downstream transcriptional programs, often by disrupting autoinhibitory domains or promoting ligand-independent phosphorylation and dimerization (95, 98). Those gain-of-function mutations have been found in various auto-immune diseases.

JAK1 mutations are associated with severe allergic disease, eosinophilia, and Th2-biased inflammation (95, 99). STAT3 gain-of-function mutations lead to autoimmunity, lymphoproliferation, and hypogammaglobulinemia. Mechanistic studies using overexpression systems, CRISPR murine models, and phospho-signaling assays have confirmed their pathogenicity and responsiveness to JAK inhibitors (98, 100). STAT6 gain-of-function mutations increase basal activity and IL-4/IL-13 sensitivity, promoting allergic phenotypes and, in some cases, lymphoma (96, 97).

To date, no gain-of-function mutations in JAK1, STAT3, STAT5B, or STAT6 have been identified in human endometriosis tissues, cell lines, or animal models. This remains an important area for future investigation. Introducing validated gain-of-function alleles into endometrial stromal or epithelial models could provide a powerful strategy to uncover causal mechanisms and potentially reveal novel therapeutic targets.

The JAK/STAT pathway varies by tissue context. In the eutopic endometrium, cyclical fluctuations in macrophages, neutrophils, and uterine natural killer (uNK) cells play a vital role in tissue remodeling and immune regulation (101). In endometriosis, however, these immune cell populations—particularly macrophages and neutrophils—are dysregulated, especially during the proliferative phase, suggesting a disruption in immune–neural communication (102). The JAK/STAT pathway is a key regulator of immune cell function, including the pain-related activity of macrophages. Dysregulation of this pathway—particularly through IL-23/IL-17 signaling and the TYK2-JAK2 axis—can enhance neutrophil activation and contribute to pain sensitization. Pharmacological inhibition of this pathway has been shown to reduce inflammatory responses in other autoimmune diseases and is therefore likely to be beneficial in endometriosis.