The biological centrepiece of the review is epithelial–mesenchymal transition, or EMT, the process by which epithelial cells lose their adhesive, stationary character and acquire the migratory, invasive traits of mesenchymal cells. In endometriosis, EMT is thought to be essential for the survival of endometrial cells that reflux into the pelvic cavity during menstruation and subsequently implant on peritoneal surfaces, ovaries and other ectopic sites. ZEB1 sits at the apex of this programme. It suppresses CDH1, the gene encoding E-cadherin, the principal adhesion molecule holding epithelial sheets together, and in doing so dismantles the cell–cell junctions that would otherwise keep ectopic cells anchored and vulnerable. The review details how ZEB1 accomplishes this repression by recruiting chromatin-remodelling machinery, notably the SWI/SNF ATPase subunit BRG1, to the E-cadherin promoter, effectively silencing it epigenetically. The result is a stabilised mesenchymal differentiation that permits attachment, invasion and, ultimately, the vascularisation required for a lesion to persist.

Crucially, the authors argue that ZEB1 is not merely one EMT factor among many, such as SNAI1, SNAI2 or its paralog ZEB2, but a systems-level hub. Immunohistochemical and molecular studies have repeatedly shown selective upregulation of ZEB1 in ectopic endometriotic lesions compared with matched eutopic endometrium, and its expression is particularly pronounced in deep infiltrating disease. One frequently cited clinical study found ZEB1 expression to be a potential indicator of invasive endometriosis, while a pilot investigation of different disease phenotypes has extended these observations across superficial, ovarian and deep infiltrating subtypes. Measurable ZEB levels have even been detected in plasma and peritoneal fluid of patients with endometriosis and infertility, raising the prospect of ZEB-family proteins as circulating biomarkers.

Perhaps the most consequential section of the review concerns the bidirectional crosstalk between ZEB1 and sex steroid signalling. Endometriosis is a hormone-dependent disease, and its defining therapeutic problem is progesterone resistance: lesions fail to respond to the progestational drugs used to suppress them. The review marshals evidence that oestrogen, specifically 17β-estradiol, induces ZEB1 expression, and that ZEB1 in turn suppresses progesterone receptor pathways. This creates a self-reinforcing circuit in which the oestrogen-ZEB1 axis dismantles the molecular machinery that progesterone therapy depends upon. Experimental work has demonstrated that high ZEB1 expression accompanies 17β-estradiol-induced EMT in endometriotic cells, and parallel findings from other hormone-driven diseases reinforce the mechanism: in breast cancer, ZEB1 induces oestrogen receptor-α promoter hypermethylation and confers antiestrogen resistance, and ZEB-family members have been shown to regulate endocrine therapy sensitivity through both canonical and non-canonical routes. In endometriosis, EMT itself has been shown to contribute to the downregulation of progesterone receptor expression in lesions, and the near-uniform loss of progesterone receptor isoform B in ectopic tissue is a long-standing observation that the ZEB1 framework now helps to explain mechanistically.

The review also devotes substantial attention to the non-coding RNA dimension of ZEB1 regulation, describing a multilayered feedback architecture that locks the mesenchymal state in place. The miR-200 family of microRNAs normally targets the 3′ untranslated regions of ZEB1 and ZEB2 transcripts, holding EMT in check. In ectopic lesions, this double-negative feedback loop is subverted: ZEB1 represses miR-200 transcription, and the resulting loss of miR-200 pressure allows ZEB1 protein to accumulate. Long non-coding RNAs add another tier. The lncRNA AFAP1-AS1, for example, promotes EMT in endometriosis in a ZEB1-correlated manner, and the metastasis-associated transcript MALAT1 has been implicated in the same circuitry, with miR-200c suppressing endometriotic progression in vitro and in vivo by targeting it. Circular RNAs complete the picture. The circRNA circZFPM2 has been shown to promote EMT by sponging miR-205-5p and thereby releasing ZEB1 from repression, while hsa_circ_0063526 acts through the miR-141-5p/EMT axis and circATRNL1 acts upstream by upregulating the EMT cofactor YAP1. Together these competing endogenous RNA networks—a concept also validated in metastatic cancer by J Clin Invest work—build a ceRNA web that perpetuates ZEB1 expression long after the initial pro-EMT stimulus has passed.

The authors then connect ZEB1 to the two great downstream consequences of endometriotic lesions: chronic inflammation and fibrosis. Through interactions with the TGF-β pathway—upstream signals such as TGF-β1 activate SMAD2/3, which cooperate with ZEB1 to drive the mesenchymal programme—ZEB1-linked cells reshape the lesion microenvironment. Fibroblast-to-myofibroblast transdifferentiation, marked by α-smooth muscle actin expression, generates the dense extracellular matrix characteristic of endometriotic implants, and analogous MRTF-A–ZEB1–IRF9 axes have been documented in renal fibrosis. Inflammation completes the loop: pro-inflammatory cytokines such as TNF-α, IL-6 and IL-10, and peritoneal fluid cytokine profiles that differ across endometriosis subphenotypes, feed back into EMT signalling through MAPK, ERK, PI3K/AKT and NF-κB pathways, while immune evasion mechanisms—including indoleamine 2,3-dioxygenase-mediated suppression of natural killer cell cytotoxicity—shield ectopic tissue from immune clearance. ZEB1’s own roles in immune cell biology and in macrophage efferocytosis and mitochondrial dynamics add further dimensions to this immunological interplay.

A distinctive strength of the review is its engagement with modern genomics and the heterogeneity it has revealed. Single-cell transcriptomic analyses of endometriosis, published in Nature Genetics and the Journal of Pathology, have identified distinct hormonal, immunologic and inflammatory signatures among the cell populations constituting lesions, and spatial transcriptomics is beginning to map how intermediate fibroblast and myeloid cell distributions shape lesion architecture. ZEB1 expression, the authors note, is not uniform: it varies by lesion subtype, anatomical site and microenvironmental context, which helps explain why superficial peritoneal, ovarian endometrioma and deep infiltrating disease behave so differently and respond so unevenly to therapy. This heterogeneity argues strongly against a one-size-fits-all anti-ZEB1 strategy and supports the emerging precision-medicine framing of the oestrogen-ZEB1-TGF-β axis as the central therapeutic target.

The review is refreshingly candid about the translational paradox at the heart of any ZEB1-directed therapy. Far from being a purely pathological molecule, ZEB1 has indispensable physiological functions in the female reproductive tract. In vitro studies show that ZEB1 modulates endometrial receptivity through EMT in endometrial epithelial cells, and work in mice demonstrates that it promotes EMT of endometrial epithelium and plays a critical role in embryo implantation. ZEB1 is also detected in granulosa cells of women undergoing IVF, regulates wound angiogenesis and closure, participates in corneal homeostasis, and contributes to endometrial repair during menstruation through epithelial migration and mesenchymal–epithelial transition. Blanking ZEB1 systemically, therefore, risks impairing fertility, tissue regeneration and wound healing—the very outcomes clinicians are trying to protect. Any therapeutic strategy would need to be lesion-specific, temporally controlled and carefully titrated, perhaps by targeting upstream oestrogen-driven induction, the TGF-β/ALK5 arm, the non-coding RNA sponges, or post-translational stabilisation mechanisms such as ZEB1 acetylation, phosphorylation and ubiquitin-proteasome turnover via regulators like USP51 and SIAH1/2.

The authors also stress the need for better experimental models to establish causal rather than merely correlative relevance. shRNA- and siRNA-based knockdown of ZEB1 in endometriotic cells, three-dimensional patient-derived endometriosis models for drug evaluation, and multi-omics approaches that integrate transcriptomic, epigenomic and proteomic data—including recent ubiquitination-focused studies of endometriosis fibrosis—are all highlighted as tools that could convert the ZEB1 hypothesis into testable interventions. Biomarker development is another avenue: ZEB-family levels in plasma and peritoneal fluid, in combination with existing miRNA signatures, could one day support non-invasive diagnosis, a long-standing unmet need given that current detection still relies on laparoscopy.

Ultimately, the review’s central claim is that the oestrogen–ZEB1–TGF-β axis functions as a signalling hub through which the hormonal, inflammatory and epigenetic drivers of endometriosis converge and perpetuate one another. By identifying ZEB1 as the point of integration, the authors provide a mechanistic scaffold that could explain progesterone resistance, fibrotic progression and recurrence within a single framework, and they chart a cautious but concrete path toward mechanism-based, lesion-specific precision therapies. For a disease that has historically been managed with blunt hormonal and surgical instruments, the prospect of intervening at the level of a single, druggable transcriptional circuit represents one of the more compelling conceptual advances in endometriosis research in recent years.

PAK5, a serine/threonine kinase that has been implicated in various cellular processes, including cell proliferation, migration, and survival, has emerged as a key in understanding the progression of endometriosis. When the endometrial cells migrate and proliferate outside the uterus, they often acquire metabolic adaptations that facilitate their survival in the ectopic environment. The recent studies highlight that PAK5 is instrumental in promoting anaerobic glycolysis in endometriotic cells through its interaction with pyruvate kinase M2 (PKM2). The phosphorylation of PKM2 by PAK5 is a pivotal step that not only stabilizes PKM2 protein levels but also enhances its glycolytic activity, which is critical for supporting the metabolic demands of endometriotic tissues.

As endometriosis advances, the demand for cellular energy increases, necessitating a shift from aerobic respiration to anaerobic glycolysis, even in the presence of oxygen—a phenomenon known as the Warburg effect. The research established that PAK5 enhances this metabolic switch, allowing endometriotic cells to thrive and grow in unfavorable conditions. This finding emphasizes the potential of targeting PAK5 and its associated pathways in treating endometriosis by disrupting the metabolic adaptations that support ectopic tissue survival.

In their investigations, researchers meticulously examined how PAK5 impacts endometrial cellular functions. Utilizing various experimental approaches, including cell culture systems and immunohistochemical techniques, they were able to elucidate the relationship between PAK5 and PKM2. The studies revealed that increased expression of PAK5 correlates with elevated PKM2 levels, reinforcing the notion that PAK5 serves as a positive regulator in the context of endometriosis.

One of the most compelling aspects of this research is the potential implications for therapeutic strategies aimed at endometriosis management. The application of a small-molecule inhibitor for PAK, named GNE 2861, demonstrated a marked reduction in cellular proliferation and migration. This effect suggests that pharmacological inhibition of the PAK5 pathway could yield significant therapeutic benefits, reducing the disease’s progression and alleviating its associated symptoms.

In addition to the molecular focus, the study extensively explored the broader implications of targeting the PAK5-PKM2 axis as a novel therapeutic strategy. By potentially modulating PAK5 activity, clinicians may find a pathway to influence PKM2 activity and glycolysis favorably, ultimately seeking to improve treatment outcomes for women suffering from endometriosis. This approach could provide a critical intervention point in a field that has largely been reliant on managing symptoms rather than altering disease progression.

Moreover, the findings of this research underscore the importance of understanding the pathogenic mechanisms of endometriosis at a cellular level. Authoritative insights into the role of PAK5 contribute substantially to the existing body of knowledge, offering a foundation for future studies aimed at unraveling the complexities of this disorder. As researchers continue to delineate the molecular underpinnings of endometriosis, it is increasingly evident that targeted therapies could radically transform how this condition is treated.

The breadth of research into endometriosis highlights the urgency of developing effective, mechanisms-based treatments. As therapeutic options remain limited, the scientific community’s focus on signaling pathways and metabolic adaptations signals a pivotal shift in addressing this complex condition. The ongoing investigation into PAK5’s role in endometriosis not only provides hope for effective interventions but also reinforces the need for continued exploration in this field.

Overall, this research bridges a significant gap in the current understanding of endometriosis pathophysiology. It positions PAK5 as a promising therapeutic target, with the required mechanistic insights to inform future clinical applications. By further elucidating these pathways, researchers contribute to a growing body of work that aims to enhance the quality of life for women affected by this challenging reproductive disorder.

The ongoing exploration of endometriosis and its underlying mechanisms promises to illuminate new pathways for diagnosis and treatment. As the scientific community continues to engage with and investigate this condition, it is clear that the pioneering work surrounding PAK5 and metabolic regulation will serve as a critical cornerstone for advancements in treating endometriosis effectively.

Through a comprehensive understanding of the molecular interactions at play, the research paves the way for innovative treatment strategies that could significantly alter the future landscape of endometriosis management. The role of PAK5 and PKM2 in modulating glycolysis emphasizes the necessity for targeted therapies that address the root causes of this challenging condition.

In conclusion, this research represents a significant step forward in comprehension and treatment of endometriosis, illustrating how a deeper understanding of disease mechanisms can lead to novel therapeutic approaches. As developments in this area progress, it is anticipated that innovative strategies will emerge, ultimately improving the lives of countless women suffering from endometriosis.

Subject of Research: Not applicable
Article Title: PAK5-mediated PKM2 phosphorylation is critical for anaerobic glycolysis in endometriosis
News Publication Date: 15-Dec-2024
Web References: http://dx.doi.org/10.1007/s11684-024-1069-3
References: Not available
Image Credits: Jiayi Lu, Xiaoyun Wang, Xiaodan Shi, Junyi Jiang, Lan Liu, Lu Liu, Chune Ren, Chao Lu, Zhenhai Yu

Keywords: Health and medicine