The Role of Long Noncoding RNAs on Male Infertility: A Systematic Review and In Silico Analysis

SIMPLE SUMMARY: Male infertility is a health problem affecting a huge number of couples worldwide. For many years, scientists have focused on protein-coding genes to explore the causes and mechanisms of male infertility. In addition, noncoding regions that are transcribed but do not lead to protein production have also been proven to play an important role in many cellular processes and diseases. The exact role of long noncoding RNAs on male infertility is not well understood. In order to address this gap, we performed a systematic review of the literature using two databases, and then a bioinformatics analysis to identify the most important long noncoding RNAs in male infertility, as well as their mechanism of action. At first, we identified 625 articles, but after selecting some of them according to the criteria that we defined, our final sample comprised 20 articles. After analyzing them, many long noncoding RNAs were found to be deregulated in male infertility or specific subtypes of it, paving the way for a better understanding of the molecular mechanisms behind male infertility, or even for the improvement of diagnosis and therapy. Finally, an association was found between male infertility and cancer that requires further investigation in the future. ABSTRACT: Male infertility is a complex disorder affecting many couples worldwide. Long noncoding RNAs (lncRNAs) regulate important cellular processes; however, a comprehensive understanding of their role in male infertility is limited. This systematic review investigates the differential expressions of lncRNAs in male infertility or variations in lncRNA regions associated with it. The PRISMA guidelines were used to search Pubmed and Web of Science (1 June 2022). Inclusion criteria were human participants, patients diagnosed with male infertility, and English language speakers. We also performed an in silico analysis investigating lncRNAs that are reported in many subtypes of male infertility. A total of 625 articles were found, and after the screening and eligibility stages, 20 studies were included in the final sample. Many lncRNAs are deregulated in male infertility, and interactions between lncRNAs and miRNAs play an important role. However, there is a knowledge gap regarding the impact of variants found in lncRNA regions. Furthermore, eight lncRNAs were identified as differentially expressed in many subtypes of male infertility. After in silico analysis, gene ontology (GO) and KEGG enrichment analysis of the genes targeted by them revealed their association with bladder and prostate cancer. However, pathways involved in general in tumorigenesis and cancer development of all types, such as p53 pathways, apoptosis, and cell death, were also enriched, indicating a link between cancer and male infertility. This evidence, however, is preliminary. Future research is needed to explore the exact mechanism of action of the identified lncRNAs and investigate the association between male infertility and cancer.