1. Introduction

Endometriosis is a chronic gynecological condition in which tissue resembling the endometrium develops outside the uterine cavity. Patients may experience dysmenorrhea, chronic pelvic pain, deep dyspareunia, fatigue, infertility, and a significant reduction in quality of life. The disease has a complex pathogenesis involving several interacting mechanisms, including estrogen-dependent inflammation, immune dysfunction, progesterone resistance, angiogenesis, altered apoptosis, and epigenetic changes [1,4,18,20,21].
Despite being relatively common, endometriosis is often diagnosed late. The symptoms can differ substantially between individuals, and the severity of symptoms does not necessarily reflect the extent of the disease. Transvaginal ultrasonography and magnetic resonance imaging are useful for detecting ovarian endometriomas and deep endometriosis, but superficial peritoneal lesions can still be difficult to identify [1,23,24]. Current clinical practice increasingly allows diagnosis to be based on symptoms and imaging when appropriate, meaning that laparoscopy is no longer required in every suspected case. Even so, there remains a clear need for a sensitive and specific blood-based biomarker that could support earlier and less invasive diagnosis.

Long non-coding RNAs (lncRNAs) are generally defined as RNA molecules longer than 200 nucleotides that have little or no protein-coding capacity. Rather than being biologically inactive, they can interact with DNA, RNA, and proteins and influence processes such as chromatin remodeling, transcription, mRNA stability, translation, and intracellular signaling [6,8,12]. Their wide range of functions makes them particularly interesting in endometriosis, where several biological pathways interact rather than a single molecular mechanism being responsible for disease development.
This review considers the biological and potential diagnostic significance of lncRNAs in endometriosis, focusing particularly on MALAT1, H19, HOTAIR, MEG3, GAS5, and lncRNAs associated with extracellular vesicles.

2. Methods

2. Methods

A narrative literature review was conducted using PubMed, Scopus, and Web of Science. Search terms and concepts included endometriosis, long non-coding RNA, lncRNA, circulating RNA, extracellular vesicles, exosomes, and biomarkers. Human studies involving patients with endometriosis were considered, together with mechanistic studies that helped establish the biological plausibility of lncRNA involvement in the disease. Particular attention was given to studies examining circulating or extracellular-vesicle-associated lncRNAs and their possible diagnostic relevance.

As this manuscript was designed as a narrative review rather than a systematic review or meta-analysis, formal PRISMA screening counts, risk-of-bias assessments, and pooled estimates of diagnostic accuracy were not performed. The flow diagram presented in Figure 1 therefore illustrates the overall review process rather than representing a quantitative PRISMA flow diagram.

Figure 1. Literature identification and qualitative synthesis workflow used for this narrative review.

3. Biological Characteristics of lncRNAs

LncRNAs comprise a large and diverse group of non-coding RNA transcripts. Based on their genomic location and relationship to protein-coding genes, they can be broadly categorized as intergenic, intronic, antisense, sense-overlapping, or bidirectional transcripts [6,8,12]

Their functions are similarly diverse. Some lncRNAs act as molecular scaffolds, bringing proteins and chromatin-associated molecules together. Others interact with transcription factors or chromatin-modifying complexes and thereby influence gene transcription. At the post-transcriptional level, lncRNAs can affect mRNA stability and translation. Some also function as competing endogenous RNAs by binding microRNAs and altering the availability of those microRNAs to regulate their target messenger RNAs [6,8,9,12].

This range of functions provides a plausible explanation for why lncRNAs may be involved in endometriosis. The disease itself involves several overlapping processes, including inflammation, hormonal signaling, immune responses, angiogenesis, cellular proliferation, apoptosis, and fibrosis [18-21].

4. Why lncRNAs May Be Relevant to Endometriosis

4.1 Inflammation

Inflammation plays a central role in both the development and persistence of endometriotic lesions. LncRNAs can influence inflammatory signaling pathways, including nuclear factor-κB and cytokine-related networks. Changes in lncRNA expression may therefore contribute to the inflammatory environment surrounding endometriotic lesions [18,21].

4.2 Angiogenesis

For ectopic endometrial tissue to survive and expand, it must establish an adequate blood supply. Several lncRNAs have been linked to angiogenic pathways and signaling involving vascular endothelial growth factor. This raises the possibility that abnormal lncRNA activity could contribute to the vascularization and continued growth of endometriotic lesions [18,20].

4.3 Estrogen Signaling

Endometriosis is strongly dependent on estrogen. Abnormal estrogen metabolism and signaling are thought to contribute to both lesion growth and inflammation, while lncRNAs may influence estrogen receptor activity and the expression of estrogen-responsive genes [5,18].

4.4 Cellular Proliferation and Apoptosis

expression through transcriptional, post-transcriptional, epigenetic, and competing endogenous RNA mechanisms. MALAT1, H19, HOTAIR, MEG3, and GAS5 have been investigated in endometriotic tissue and, in selected studies, in serum, plasma, or extracellular vesicles. These molecules appear to participate in pathways involving inflammation, angiogenesis, cellular proliferation, apoptosis, estrogen signaling, invasion, and tissue remodeling. Their relative stability in biological fluids makes circulating lncRNAs attractive candidates for non-invasive biomarker development. However, substantial heterogeneity exists in patient selection, disease stage, menstrual-cycle phase, specimen type, RNA extraction, normalization, and analytical methodology.

Conclusion: LncRNAs represent promising molecular candidates for non-invasive diagnosis and potentially disease monitoring in endometriosis. Nevertheless, current evidence is not sufficient for routine clinical implementation. Large prospective multicenter studies using standardized pre-analytical and analytical protocols, clinically relevant control groups, and independent external validation are required before lncRNA-based biomarkers can be incorporated into clinical practice.

Keywords: Endometriosis; long non-coding RNA; lncRNA; biomarker; non-invasive diagnosis; MALAT1; H19; HOTAIR; MEG3; GAS5; extracellular vesicles.

The establishment of an endometriotic lesion depends partly on the ability of ectopic cells to survive and proliferate. Alterations in lncRNA expression have been linked to pathways involved in cell-cycle regulation, proliferation, and apoptosis [6,12,18]. These changes may allow ectopic endometrial cells to survive in an environment in which they would otherwise undergo programmed cell death.

4.5 Invasion and Tissue Remodeling

Endometriotic cells have invasive properties and interact with the surrounding extracellular matrix. Some lncRNAs have been associated with epithelial-mesenchymal transition and pathways involved in extracellular-matrix remodeling. Such effects could contribute to implantation, invasion, and progression of endometriotic lesions [18,19,23].

5. Results: Evidence for lncRNAs in Endometriosis

The literature reviewed provides consistent evidence that altered lncRNA expression is associated with several molecular processes involved in endometriosis, although the findings are not completely uniform. MALAT1, H19, HOTAIR, MEG3, and GAS5 are among the most frequently discussed candidates. Their reported expression patterns vary depending on the tissue or biological fluid examined and on the design of individual studies. For this reason, the findings were considered qualitatively rather than combined into pooled estimates of diagnostic accuracy.

5.1 Circulating and Extracellular-Vesicle-Associated lncRNAs

One of the most appealing features of lncRNAs from a clinical perspective is that some can be detected in peripheral blood. Circulating lncRNAs may be present as free RNA associated with proteins or may be transported within extracellular vesicles. Exosomes and other extracellular vesicles can protect their RNA cargo from degradation, potentially allowing these molecules to remain detectable in biological fluids [14,15].

This has led to interest in circulating and exosomal lncRNAs as possible diagnostic biomarkers for endometriosis. However, simply detecting an lncRNA in blood does not demonstrate that it is clinically useful. A diagnostic biomarker needs to reliably distinguish patients with endometriosis from appropriate control populations and should ideally demonstrate similar performance in independent cohorts

It is also important not to assume that changes observed in endometriotic tissue will necessarily be reproduced in blood. Circulating RNA is influenced by its release from different tissues, transport, degradation, and clearance. As a result, tissue expression and circulating expression may reflect different aspects of disease biology [14,15].

5.2 Candidate-Specific Findings

MALAT1: MALAT1 is one of the most extensively studied mammalian lncRNAs. In endometriosis, changes in MALAT1 expression have been associated with cellular proliferation, migration, angiogenesis, inflammation, and regulatory RNA networks. Its expression can be measured using techniques such as qRT-PCR, making it an appealing candidate for biomarker research. Nevertheless, reported diagnostic performance has varied between studies, and evidence specifically supporting its use as a circulating biomarker remains less developed than the broader evidence concerning its biological role [6,12].

H19: H19 is an imprinted lncRNA involved in developmental and regulatory processes. It has attracted interest in endometriosis because of its reported links to estrogen-related signaling and cellular proliferation. Experimental studies suggest that abnormal H19 expression may affect the behavior of endometriotic cells through interactions with microRNAs and downstream signaling pathways. However, differences in sample type and normalization methods make it difficult to compare results directly between studies.

HOTAIR: HOTAIR is a trans-acting lncRNA that can interact with chromatin-modifying complexes. In endometriosis, altered HOTAIR expression has been associated with invasion, proliferation, and epigenetic regulation.

These findings support a possible biological role for HOTAIR, but they do not yet demonstrate that it can function as an independent diagnostic biomarker [6,9].

MEG3: MEG3 has been associated with inhibition of cellular proliferation and promotion of apoptosis in several biological settings. Studies of endometriosis have reported altered MEG3 expression, while experimental findings suggest that reduced MEG3 activity could contribute to abnormal cell survival and proliferation. Whether MEG3 can be reliably measured in circulation and used diagnostically remains to be established in well-designed human studies.

GAS5: GAS5 is involved in cell growth, apoptosis, and signaling related to steroid receptors. Changes in GAS5 expression may affect the survival and apoptotic behavior of ectopic endometrial cells. Although its detection in circulation makes GAS5 an interesting biomarker candidate, current evidence is not sufficient to support its use as a standalone diagnostic test.

5.3 Exosomal and Extracellular-Vesicle-Associated lncRNAs

Extracellular vesicles contain a range of molecular components, including RNA, proteins, and lipids, and are involved in communication between cells [14,15]. Because lncRNAs contained within these vesicles may be protected from degradation, extracellular vesicles have attracted considerable interest as a possible source of minimally invasive biomarkers.

In endometriosis, RNA contained within extracellular vesicles may provide information about communication between endometriotic lesions and surrounding tissues. However, research in this area is complicated by substantial methodological differences. Various techniques are used to isolate extracellular vesicles, and the resulting preparations may differ in their composition and biological properties. Standardization of vesicle isolation, characterization, RNA extraction, and normalization is therefore essential if findings from different studies are to be compared reliably [14-16].

5.4 Overall Diagnostic Implications

At present, the available evidence does not support a single, reproducible circulating lncRNA signature with a clinically established sensitivity, specificity, or diagnostic threshold. Instead, the findings suggest that a combination of several lncRNAs may eventually be more useful than an individual transcript. Such a model could potentially be combined with clinical characteristics, imaging findings, or established biomarkers such as CA-125 to improve diagnostic discrimination.

6. Summary of Major lncRNA Candidates

Table 1. Principal lncRNA candidates discussed in the reviewed literature.