**5. Summary and Perspectives**

In recent years, a growing number of studies have implicated the abnormal expression of specific lncRNAs with various aspects of endometriosis pathogenesis. This altered expression may be due to genetic predisposition or an unknown environmental trigger and affect pathogenetic processes including EMT, endometriosis cell stemness, angiogenesis, lesion establishment and growth, endometriosis cell survival, proliferation and invasion, oxidative stress, autophagy, and endometrial receptivity (summarized in Figure 4). Evidence for the role of lncRNAs has mainly come from large-scale transcriptome studies comparing normal and diseased tissue, followed by validation studies of a small number of candidate lncRNAs. These studies can be valuable for uncovering potential novel players in endometriosis but often have weaknesses that should be considered including small sample size, incomplete clinical information on patient samples, and inappropriate controls (Table 1, Table S1). A general weakness of these studies is that they do not assess the complexity of the disease to take into account different lesion types, the stage or severity of the disease, or the effect of hormone status or age of the patient. The vast majority of lncRNAs revealed in these studies remain unvalidated by an independent method or by functional studies. One challenge for future work is to prioritize lncRNAs identified in these studies for validation and then conduct further functional studies to determine their role in endometriosis and their possible use as biomarkers or targets for treatment.

One avenue of endometriosis research that should be pursued in the future is the connection between genetic variants and abnormal lncRNA expression that affects aspects of endometriosis pathogenesis. The majority of disease-associated SNPs in GWAS studies, including those investigating endometriosis, are in non-coding regions. The hypothesis that these SNPs may affect lncRNA function is supported by a number of studies in endometriosis, with SNPs in or near lncRNAs including *HOTAIR, MALAT1, CDKN2B-AS, PCAT1,* and *LINC00339* affecting their expression and regulation of genes and the

endometriosis phenotype [28–32]. The possibility that other non-coding SNPs associated with endometriosis may also affect the disease via lncRNAs should be investigated.

**Figure 4.** Phenotypical changes caused by altered expression of lncRNAs in endometriosis. Altered expression of lncRNAs in endometriosis is involved in the regulation of numerous processes known to be associated with the pathogenesis of the disease. These processes include EMT, endometriosis cell stemness, angiogenesis, lesion establishment and growth, endometriosis cell survival, proliferation and invasion, oxidative stress, autophagy, and endometrial receptivity.

In vitro cell culture models and in vivo animal models are valuable systems that enable the mechanism of action and function of individual lncRNAs to be investigated experimentally. However, a weakness of some studies investigating endometriosis, including those investigating the role of lncRNAs, is that the available in vitro and in vivo models may not always represent all aspects of the disease accurately. Therefore, it should be a priority for the field to continue to strive for improved models to investigate the disease.

To conclude, genome-wide genomic and transcriptomic studies have implicated numerous lncRNAs in a wide range of diseases, including in endometriosis. The challenge remains to distinguish the lncRNAs that play a relevant role in the disease from those that are merely associated with the transcriptional changes in the disease and to functionally show their role.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/ijms222111425/s1.

**Author Contributions:** Conceptualization, Q.J.H., K.P. and I.Y.; methodology, Q.J.H., K.P. and I.Y.; data curation, Q.J.H., K.P. and I.Y.; writing—original draft preparation, Q.J.H., K.P. and I.Y.; writing—review and editing, A.P., L.K., H.H. and R.W.; visualization, Q.J.H., K.P. and I.Y.; supervision, I.Y.; funding acquisition, H.H. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was co-funded by the Ingrid Flick Foundation (grant no. FA751C0801), which played no role in the review design and analysis, decision to publish, or preparation of the manuscript.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
