Gene regulation by non-Coding RNAs in infertility: a mechanistic review.

Introduction

The inability of a woman who has never conceived to conceive after at least 12 months of consistent, unprotected sexual activity is known as primary infertility, according to the World Health Organization (WHO). The inability of a woman who has already conceived to conceive a child after 12 months of consistent, unprotected sexual activity, regardless of the pregnancy’s result, is known as secondary infertility [ 1 – 3 ]. For both men and women, infertility has significant physical, psychological, and social repercussions, making it a significant worldwide public health concern. It considerably lowers personal well-being and quality of life, making it one of the top five most severe impairments in the world. The social and cultural effects of infertility typically disproportionately impact women, who are also more likely than men to be blamed and stigmatized [ 4 ]. Men account for more than half of infertility cases [ 5 ]. Significant geographical differences in infertility trends are noted in reports. In certain areas, such as North Africa and the Middle East, primary infertility is far more common, while secondary infertility is still rather rare. In contrast, the trend in areas such as Central and Western Europe shows that secondary infertility is more common and initial infertility is less common [ 6 ]. Global research indicates that secondary infertility is often more prevalent than original infertility; however, reported rates vary according to study design, chronology, and geographic area. A pooled WHO analysis of data collected between 1990 and 2010 estimated secondary infertility at 9–33% and primary infertility at 1–3% worldwide [ 7 ]. Later population-based surveys (2009–2010) confirmed this pattern, reporting secondary infertility at 7–18% and primary infertility at 1–3% [ 8 ]. Regional studies demonstrate wide heterogeneity: in women, prevalence has ranged from < 6% in some Western European countries to >16% in parts of Sub-Saharan Africa, depending on nation and study period [ 9 ]. A meta-analysis of post-1990 surveys further found infertility rates of 3–17% in high-income regions and 7–9% in low- and middle-income regions, reflecting differences in diagnostic criteria, environmental exposures, and access to reproductive healthcare [ 10 ]. Together, these data highlight a consistent global pattern of higher secondary infertility but also underscore the importance of methodological and regional factors when comparing prevalence estimates. Infertility shows significant variation within and between nations throughout continents, rather than following a consistent trend. Additionally, there aren’t many thorough comparative studies that look at long-term patterns in primary and secondary infertility in both men and women over lengthy periods of time at the regional and international levels. The increasing worldwide prevalence of infertility, including both main and secondary types, underscores the critical need to identify its genetic determinants. Epidemiological patterns indicate that male and female variables often intersect, suggesting common biological mechanisms. Non-coding RNAs (ncRNAs) are among the most significant regulators, connecting environmental and genetic factors to the essential processes of gametogenesis, fertilization, and embryonic development. Integrating molecular insights with population-level data is crucial for converting epidemiological findings into specific diagnostic and treatment solutions.

The exact temporal and spatial expression of genes necessary for effective gametogenesis, fertilization, embryonic development, and sexual differentiation is orchestrated by gene regulation, which is crucial to reproductive biology. In order to guarantee the correct development and operation of reproductive organs, the precise course of meiosis, balanced hormone production, and the coordinated integration of reproductive physiological systems, gene expression is regulated by complex regulatory networks. The functional competence and developmental integrity necessary for fertility and successful reproduction are supported by this intricate regulation. An outline of the gene regulatory processes implicated in crucial phases of reproduction, supported by data from recent scientific research, is provided below [ 11 ]. Only around 2% of human genomic DNA sequences are found to encode functional proteins, although 93% of these sequences are translated into RNA molecules. Notably, ncRNAs, which have a variety of regulatory functions beyond protein synthesis, are produced by the bulk of the transcribed sequences (about 90%) [ 12 , 13 ]. The bulk of noncoding RNAs in these cells is classified as either small noncoding RNAs (sncRNAs), which are less than 200 nucleotides, or long noncoding RNAs (lncRNAs), which are longer than 200 nucleotides. The several classifications of sncRNAs can be further separated into regulatory and structural categories. Interestingly, microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), which are both essential for regulating gene expression, are included in the category of regulatory sncRNAs [ 14 , 15 ]. Significant progress has been made in the last 20 years in comprehending the roles of short noncoding RNAs in cellular biology. Nevertheless, in recent times, there has been a growing emphasis on studying lncRNAs, which have become essential elements of the gene regulation network. Previously thought of as transcriptional “noise,” lncRNAs are now understood to be important regulators involved in the pathophysiology of several illnesses as well as normal physiological activities [ 16 , 17 ]. Numerous investigations have shown that noncoding RNAs are essential for controlling oogenesis and spermatogenesis, impacting the intricate molecular processes that control the maturation and development of both male and female gametes [ 18 ]. The importance of ncRNAs as major regulators of many biological processes has been brought to light in recent years by mounting evidence. ncRNAs alter gene expression on several levels during spermatogenesis and follicular development, impacting crucial processes such as meiosis progression, cellular proliferation, differentiation, and genomic imprinting [ 19 , 20 ]. By examining their role in gene regulatory networks, reproductive pathophysiology, and underlying disease processes, this study aims to clarify the role of noncoding RNAs ncRNAs in infertility. It also highlights how useful ncRNAs are becoming as therapeutic targets and diagnostic indicators. The debate, which covers infertility in both men and women, synthesizes recent research findings to give a thorough review of what is already known and to suggest prospective avenues for further study.

Classification and biological functions of noncoding RNAs in reproduction

Overview of major classes of NcRNAs

Based on their average length, regulatory ncRNAs are often divided into two groups: lncRNAs, which have transcripts longer than 200 nucleotides, and sncRNAs, which have transcripts shorter than 200 nucleotides. miRNAs, small interfering RNAs (siRNAs), and piRNAs are the three main subclasses of tiny ncRNAs. However, certain ncRNAs, such as circular RNAs (circRNAs), enhancer RNAs (eRNAs), and promoter-associated transcripts (PATs), have varying lengths that enable them to be categorized into many categories at the same time.

The most prevalent class of tiny ncRNAs produced from transcribed hairpin loop structures is called miRNAs [ 21 – 24 ]. They facilitate gene silencing at the post-transcriptional stage and control gene expression in the cytoplasm and nucleus via distinct methods [ 21 ]. miRNAs have been a major area of study for many years since they are key regulators in the complex web of RNA interactions. With the addition of 48 additional miRNA species in the most recent release of miRBase (version 22), the repository now contains 38,589 hairpin precursor sequences and 48,860 mature miRNAs. These entries span 271 species, spanning mammals, plants, unicellular algae, and viruses [ 25 ].

siRNAs are a type of double-stranded RNA molecule that play a critical role in the RNA interference (RNAi) process. siRNAs are divided into two primary subtypes based on where they come from: endogenous siRNAs (endo-siRNAs), which are primarily transcribed from transposable elements (TEs) and originate from the host genome, and exogenous siRNAs (exo-siRNAs), which are derived from external nucleic acids introduced artificially or through viral infections [ 26 , 27 ]. The class of siRNAs found in plants is highly varied and includes subtypes such as heterochromatic siRNAs (hc-siRNAs) and trans-acting siRNAs (tas-siRNAs) [ 28 ], Long siRNAs (lsiRNAs) [ 28 ], repeat-associated siRNAs (ra-siRNAs), and naturally occurring antisense siRNAs (nat-siRNAs) that are also found in mammals [ 29 ].

piRNAs, a class of small noncoding RNAs specific to animals, are named for their association with PIWI proteins. Two main biogenetic pathways produce mature piRNAs: the primary pathway involves the processing of precursor transcripts from specific genomic regions called piRNA clusters by PIWI proteins; the secondary “ping-pong” cycle amplifies and matures the piRNAs, improving their sequence specificity and functional activity [ 30 , 31 ]. Dicer-independent processing of single-stranded RNA precursors distinguishes piRNAs from miRNAs and siRNAs [ 32 ], and they only work by attaching themselves to PIWI proteins [ 33 ]. Silencing their targets at the transcriptional and post-transcriptional stages, piRNAs bind to PIWI proteins to create piRNA-induced silencing complexes [ 34 ]. Endo-siRNAs have a similar function in TE suppression in animals as endo-siRNAs do in plants by silencing TEs. Nonetheless, the piwi-interacting RNA (piRNA) pathway is the major and most efficient defensive mechanism against transposon activity in animal germ cells, and it is essential for preserving genomic integrity during reproduction [ 35 ].

RNA transcripts longer than 200 nucleotides that are incapable of coding proteins are known as long noncoding RNAs, or lncRNAs. Five different subcategories of lncRNAs may be distinguished based on their chromosomal location in relation to protein-coding genes [ 36 ]. Both DNA strands in the intergenic regions between protein-coding genes transcribe long intergenic noncoding RNAs, or lincRNAs. The intronic regions of protein-coding genes are the only source of long intronic noncoding RNAs. Sense lncRNAs include sequences that overlap with exons and are transcribed from the same (sense) strand as genes that code for proteins. Antisense lncRNAs, on the other hand, are transcribed from the opposite (antisense) strand and frequently overlap with the exonic or intronic portions of genes that code for proteins. Through intronic areas, they can even span complete protein-coding sequences. Last but not least, bidirectional lncRNAs are located next to a protein-coding gene on the other strand, where transcription starts nearby but moves in the other direction [ 37 ]. lncRNAs can be divided into two groups based on how they affect genomic DNA: cis-acting lncRNAs (cis-lncRNAs), which affect the expression of genes that are close to one another, and trans-acting lncRNAs (trans-lncRNAs), which affect the expression of genes that are farther apart in the genome [ 38 ]. Small ncRNAs like miRNAs, piRNAs, and snoRNAs might be produced by further processing certain lncRNAs [ 39 ].

Recently, a unique class of noncoding RNAs derived from active transcriptional enhancer regions has been discovered: eRNAs. Despite having similar lengths and no capacity to code for proteins, eRNAs and lncRNAs share several transcriptional traits, including the ability to produce both sense and antisense transcripts via bidirectional transcription [ 40 – 42 ]. Enhancer region bidirectional transcription produces somewhat shorter (0.5–2 kb) and non-polyadenylated eRNAs (polyA-eRNAs) [ 43 ], although polyadenylated eRNAs (polyA + eRNAs) and lengthy (>4 kb) eRNAs are often unidirectionally transcribed from enhancers [ 44 ]. Multiexonic polyA + eRNAs (meRNAs) are eRNAs produced by transcription initiation at enhancers in intragenic regions [ 42 , 45 ]. Although eRNAs and lncRNAs have certain traits, eRNAs are unique in that they have a 5′ cap structure yet are intrinsically unstable, having noticeably short half-lives. The exosome complex quickly breaks down eRNAs, in contrast to many lncRNAs, highlighting their ephemeral nature and functional difference from more stable lncRNA transcripts [ 46 – 51 ].

Because of their covalently closed-loop architectures, circRNAs are a special family of endogenous noncoding RNAs. CircRNAs have been known for a number of decades, but new developments in deep sequencing and bioinformatics techniques have significantly raised scientific interest in them [ 52 ]. The size of circRNAs varies greatly, ranging from around 100 nucleotides to more than 10,000 nucleotides. Nonetheless, most circRNAs found in plants and animals usually have a length of a few hundred nucleotides or less [ 53 , 54 ]. Back-splicing activities create circRNAs, which are covalently closed circular molecules. Exons, introns, intergenic sequences, untranslated regions (UTRs), and even transfer RNAs (tRNAs) are among the genomic areas from which they may emerge [ 55 ]. circRNAs, like other regulatory noncoding RNAs, have several vital biological roles, such as controlling gene transcription and altering alternative RNA splicing [ 56 ], functioning as miRNA sponges or competing endogenous RNAs (ceRNAs) [ 57 , 58 ].

Functional roles of NcRNAs in male and female reproductive systems

Spermatogenesis

The process by which germ cells proliferate and differentiate into haploid male gametes is known as spermatogenesis. Since the condensation of the sperm nucleus results in a transcriptionally restrictive state that demands strict control of gene expression at the RNA level, post-transcriptional regulation becomes essential during the latter stages of spermatogenesis [ 20 , 59 ]. It has been shown that non-coding RNAs are crucial for controlling gene expression during spermatogenesis. In order to maintain healthy germ cell development, they modulate RNA stability, processing, and translation at the post-transcriptional level in addition to their transcriptional activity, where they frequently play a crucial role in chromatin remodeling complexes [ 60 ]. This intricate process can be broken down into three main phases, and it’s interesting to note that each phase has its own distinct miRNA profile. Phase I involves the mitotic proliferation and formation of spermatogonia from germ cells, Phase II involves the formation of spermatids through spermatocyte meiosis, and Phase III is spermiogenesis, which produces mature spermatozoa from spermatids. To keep things simple, we shall separate the spermatogenesis process into early (phase I) and later (phases II and III) stages:

Several miRNAs, of which miR-34c is a well-known example, have been discovered to be important regulators of germ cell self-renewal and differentiation in mammals at this period.

In particular, by directly targeting the Nanos2 gene, miR-34c promotes the switch from stem cell maintenance to differentiation in mouse spermatogonial stem cells (SSCs) [ 61 ]. Other significant miRNAs include miR-293, 291a-5p, 290–5p, and 294, whose targets are involved in cell cycle control [ 62 ]. In this way, early in mouse spermatogenesis, miR-21 inhibition promotes the germ cell [ 63 ]. The shift from undifferentiated to A1 spermatogonia is guided by additional microRNAs, particularly those belonging to the Let-7 family, which play a crucial role in controlling mouse spermatogonial differentiation. The inhibition of Lin28, a crucial component that preserves the undifferentiated state and promotes the development of differentiation, mediates this process [ 64 ], whereas others, like miR-146, are essential for maintaining this species’ spermatogonia in an undifferentiated form [ 65 ]. Several other microRNAs, such as miR-20, miR-21, and miR-106, have been found to be important modulators of the self-renewal and differentiation of SSCs. They also play important roles in preserving spermatogonial homeostasis and guaranteeing the equilibrium between proliferation and differentiation in the germ cell population [ 66 ], miR-224, which targets DMRT1 in mice to encourage SSC self-renewal [ 66 ], The commencement of spermatogonial meiosis has been linked to miR-202-3p, whereas miR-10b targets the transcription factor KLF4 in mice to promote spermatogonial SSC self-renewal, which affects the equilibrium between germ cell maintenance and differentiation [ 67 , 68 ].

In mammals, several lncRNAs have been found to be important regulators of the development of male germ cells. Notably, Spga-lncRNA1 and Spga-lncRNA2, two spermatogonia-specific lncRNAs, have been identified as critical for maintaining the stemness of SSCs and are crucial for maintaining the progenitor cells’ ability to self-renew [ 69 ]. One molecular marker that has recently been found to be essential for the preservation of SSCs is lncRNA-033862. This lncRNA is extensively expressed in mouse SSCs and is controlled by glial cell line-derived neurotrophic factor (GDNF) signaling. It is essential for regulating the cells’ self-renewal, survival, and general upkeep, especially when these functions are impaired [ 70 ].

This stage includes spermiogenesis as well as the meiotic stages. Throughout this process, the roles of miRNAs in mammals have been well described. Although its function in regulating germ cells and SSCs has been previously identified, miR-34c also has a unique function in regulating apoptosis in spermatocytes and round spermatids [ 71 ]. It has been proposed as a modulator of the NOTCH signaling system, which regulates the differentiation of germ cells [ 72 ]. Remarkably, the mouse embryo’s first cell division also depends on miR-34c in spermatozoa [ 73 ]. The miR-449 cluster is another microRNA family that has been linked to the control of meiotic and post-meiotic processes in the latter phases of spermatogenesis. This cluster’s crucial involvement in germ cell development is shown by the fact that its overexpression is necessary for the start of meiosis in murine spermatogenesis [ 74 ]. Through its targets, this miR also contributes to germ cell apoptosis: AFT1 and BCL2 [ 68 ]. Certain miRNAs, including miR-122 and 469, control protamine targeting and chromatin condensation during the chromatin remodeling phase [ 75 ].

The importance of lncRNAs in the latter phases of spermatogenesis has been highlighted by recent studies. The transcriptional control of genes unique to this stage of germ cell development has been linked to the important roles of lncRNA-Tcam1 and lncRNA-HSVIII in pachytene spermatocytes. Furthermore, certain lncRNAs have specialized functions. For instance, Tsx (testis-specific X-linked) is known to control apoptosis in mouse pachytene spermatocytes, highlighting its significance in preserving germ cell viability [ 76 ]. Some lncRNAs have been linked to post-transcriptional regulatory roles at this stage of spermatogenesis. By interacting with tubulin, for example, Tubulin Cofactor A (TBCA) contributes to microtubule dynamics and facilitates the microtubule rearrangement necessary for appropriate spermatid maturation [ 77 ]. On the other hand, nothing is known about the role of lncRNAs in human spermatogenesis. Notably, NLC1-C has been linked to male infertility because it affects important regulatory pathways in the formation of human germ cells by modulating miRNA expression through interactions with RNA-binding proteins [ 78 ].

Oogenesis

One of the most intricate and tightly controlled cellular differentiation routes in females is oogenesis, the biological process that results in a fertile ovum and is crucial for oocyte growth. Differentiation and related morphological changes are tightly controlled by molecular mechanisms, so any dysregulation in the expression of important genes can have a significant impact on the developmental fate of dominant versus subordinate follicles (DFs vs. SFs) [ 79 – 81 ].

The function of ncRNAs in post-transcriptional control of oogenesis has attracted more interest in recent years. Characterizing small RNA populations in the ovary, its component tissues, and particular gonadal cell types was the main focus of early research. miRNAs, which are highly conserved short noncoding RNAs, have been the subject of the majority of studies on ncRNAs in oogenesis and ovarian function. For the most part, knockout (KO) investigations in murine models have provided functional insights into their activities. Conditional knockout (cKO) models have been created to examine the general roles of miRNAs in the ovary due to the crucial roles played by DROSHA-DGCR8 and DICER proteins in miRNA production. The crucial role of miRNAs in important reproductive processes, including folliculogenesis, oocyte maturation, and ovulation, has been convincingly demonstrated by these models. Additionally, miRNAs are essential regulators in a number of phases of ovarian development and function, including follicular growth, oocyte maturation, ovulation, corpus luteum formation in mammals, and the assembly of primordial follicles and the transition from primordial to primary follicles. Accordingly, the ovary’s miRNA expression patterns show a great deal of variation based on the physiological function, cell type, and estrous cycle phase. The expression patterns of these regulatory molecules in the female gonads of different species have been outlined by extensive miRNA profiling investigations conducted across mammalian ovarian tissues [ 82 – 86 ].

Multiple reproductive abnormalities, including decreased oocyte maturation, disturbed follicular development and ovulation, heightened rates of follicular atresia, and eventually infertility, are caused by conditional deletion of Dicer1 exclusively in mammalian follicular granulosa cells (GCs) [ 87 – 89 ]. Remarkably, new data indicate that a single microRNA acting via a canonical route may control the growth of bovine follicles during the estrous cycle, with the target gene of the miRNA playing a crucial part in coordinating this process [ 90 ]. As expected, a wide range of microRNAs target important transcription factors (TFs), such as TGF-β superfamily members, and receptors that are essential for follicular development, including the follicle-stimulating hormone receptor (FSHR) and the luteinizing hormone receptor (LHR). Normal folliculogenesis is hampered by dysregulation or abnormalities in these molecules, which also interfere with cellular signaling networks [ 91 – 93 ]. Additionally, several studies have demonstrated the involvement of certain miRNAs in various GC activities [ 94 ], for instance, proliferation [ 66 , 95 – 97 ], survival [ 98 – 100 ], terminal differentiation [ 101 ], steroidogenesis [ 96 , 102 – 104 ], with the growth of the cumulus in mammals [ 105 ]. For instance, by targeting Smad4 in mice, miRNA-224 has been shown to have a role in altering growth factor-beta-mediated mouse GCs proliferation and GC function [ 103 ]. Therefore, the selection of dominant follicles is probably influenced by microRNAs. However, there are several obstacles to functional characterization because of the intricacy of miRNA-target interactions, as well as their varied functional functions and complicated regulatory processes. Most miRNAs function in coordinated clusters, acting as fine-tuners of cellular processes and guaranteeing accurate modulation of follicular growth; however, some of them exert control over certain signaling pathways [ 106 ].

Overexpression of miR-143 in murine ovaries at 15.5 days post coitum (dpc) has been demonstrated to impede primordial follicle assembly by decreasing the proliferation of pre-granulosa cells, providing a particular example of microRNA-mediated control in primordial follicle development. On the other hand, more primordial follicles are produced when miR-376a is transfected into 18.5 dpc ovaries. Furthermore, miR-145 and miR-181a regulate the activity of activin, a recognized promoter of primordial follicle growth, whereas miR-320, miR-133, and miR-383 affect the production of estradiol (E2), which inhibits the creation of primordial follicles [ 107 ].

Analyzing miRNAs in ovarian samples verified that the ovaries of other mammals, including humans, have similar expression patterns [ 82 ], mice [ 83 , 108 , 109 ], pigs [ 84 ], sheep [ 110 ], goats [ 85 ], and cows [ 86 , 111 – 113 ]. The ovary’s functional unit in some non-mammalian vertebrates, including teleost fish, is different from that of mammals since it is not arranged around ovarian follicles. Despite the paucity of studies in these species, evidence points to a major function for ncRNAs in oogenesis. The microRNA miR-430, for example, is essential for the removal of maternal mRNAs in zebrafish during the early stages of embryonic development, underscoring its significance in post-transcriptional control in this species [ 114 ]. The possible regulatory roles of these miRNAs in teleost ovarian physiology were highlighted in 2016 when Bouchareb and colleagues used microarray analysis to uncover 66 microRNAs that are highly elevated in the ovaries of the teleost fish model, medaka [ 115 ]. This collection of variably abundant microRNAs contained miR-202. According to earlier reports, this specific miRNA is expressed in the gonads of a variety of non-mammalian species, such as chicken, frog, and rainbow trout, suggesting that it has a conserved role in a wide range of vertebrate taxa [ 116 – 118 ]. MiR-202 showed strict ovarian-predominance in medaka, according to microarray analysis, indicating that Oryzias latipes has an isomiR of miR-202–3p [ 115 ]. The authors of the same study discovered eight new miRNAs, miR-4785, miR-6352, miR-4653, miR-878, miR-487, miR-1288, miR-743, and miR-729, that are mostly expressed in the ovary. Two miRNAs, miR-4785 and miR-6352, were identified by their research as having highly specific ovarian expression. This suggests that these miRNAs have important regulatory roles in oogenesis and/or early embryonic development, perhaps through a maternal influence. Notably, miR-4785 is projected to target the fshr, whereas miR-6352 targets genes critical to ovarian regulatory pathways, such as smg8, ddx20, and ddx6.

Interplay between NcRNAs and hormonal regulation

ncRNAs, which include both miRNAs and lncRNAs, are essential modulators of the granulosa cell function, hormone signaling pathways essential for reproductive physiology, and the hypothalamic-pituitary-gonadal (HPG) axis. By precisely controlling gene expression involving hormone precursors, receptors, and transcriptional regulators, these ncRNAs within the HPG axis influence the production and release of important hormones, such as gonadotropin-releasing hormone (GnRH) from the hypothalamus and LH and follicle-stimulating hormone (FSH) from the pituitary. To ensure proper hormonal secretion, for example, certain miRNAs control the activity of neurons that produce GnRH, whereas lncRNAs control the expression of pituitary hormone genes. ncRNAs control the proliferation, differentiation, and steroidogenesis of granulosa cells in the ovary. Notably, it has been demonstrated that ncRNAs like miR-21 and the lncRNA H19 affect the manufacture of estrogen by influencing the susceptibility of granulosa cells to FSH and targeting essential enzymes like aromatase. Proper follicular growth and oocyte maturation depend on this regulatory network. In addition to ovarian function, ncRNAs also affect testicular steroidogenesis and gametogenesis and control hormone receptor expression in several reproductive organs, maintaining hormonal feedback loops and reproductive homeostasis in general. Variations in ncRNA expression or activity can cause hormone control to be disrupted in granulosa cells and the HPG axis. This can lead to several endocrine abnormalities and reproductive problems, such as infertility and polycystic ovarian syndrome (PCOS).

Regulation of the Hypothalamic-Pituitary-Gonadal (HPG) axis

Mammalian sexual phenotype is promoted by a variety of ncRNA classes [ 119 , 120 ]. Key regulators such as forkhead box L2 (FOXL2) and other genes involved in sex determination and gonadal development may be affected by antisense lncRNAs in terms of both expression and activity [ 121 ]. It has been shown that the U17 small nucleolar RNA (snoRNA) controls a short non-coding RNA that is produced from the Snhg3 gene’s introns. This regulation has an impact on the ovary’s cellular cholesterol trafficking. Thus, this regulatory axis may play a role in the regulation of the production of steroid hormones and the postnatal gonadal maturation process [ 122 ]. It is well known that miRNAs have a role in controlling the HPG axis. Notably, the time of pubertal onset has been intimately associated with the dynamics of Lin28/let-7 axis expression in the hypothalamus [ 123 ]. Lin28a and Lin28b expression levels decrease throughout the pubertal transition, with environmental variables that may postpone puberty or hinder follicular development possibly influencing Lin28b expression in the ovary [ 124 ]. FSH secretion is regulated by MiR-361-3p in a pig pituitary cell culture [ 125 ]. According to genome-wide profiling of miRNA expression in goats, miR-424-5p and miR-29a regulate muscle growth, whereas miRNAs in general significantly influence endometrial receptivity [ 126 , 127 ]. Furthermore, it has been shown that the three different phases of the cashmere goat’s hair follicle cycle exhibit markedly different levels of miRNA expression [ 128 ], as well as in the ovary between people who are pregnant and those who are not, with pregnant goats showing 294 miRNA upregulation and 113 downregulation [ 129 ].

Ovarian hormone regulation

One of the primary roles of ovarian granulosa cells is steroidogenesis, which produces and secretes steroid hormones that have a significant effect on follicular growth [ 130 , 131 ]. The milieu of follicular fluid can be altered by disturbances in the production or metabolism of steroid hormones, which can have an impact on follicular development and functional competency either directly or indirectly [ 132 ].

Steroidogenesis is regulated by ncRNAs, which can affect GCs and ovarian function. In addition to encouraging apoptosis, miR-6881-3p also influences GCs by modifying the expression of gonadotropin receptors (follicle-stimulating hormone receptor, or FSHR), luteinizing hormone/choriogonadotropin receptor, or LHCGR, and enzymes that produce steroid hormones, like cholesterol side-chain lyase (cytochrome P450 family 11 subfamily A member 1, or CYP11A1). By upregulating LHCGR mRNA and downregulating FSHR and CYP11A1 mRNA, it affects steroidogenesis [ 133 ]. Similarly, research on the lncRNA PWRN1 has demonstrated that its downregulation decreases the synthesis of progesterone and estradiol (E2) in addition to GC apoptosis, cell cycle progression, and autophagy [ 131 ]. It has also been discovered that miR-423-5p increases the amount of S-phase cells and promotes E2 secretion in its downregulated state [ 134 ]. However, miR-96-5p binds and downregulates FOXO1, which in turn controls the expression of downstream genes such as steroidogenic factor (SF)1 and cytochrome P450 family 19 subfamily A member 1 (CYP19A1), which stimulate E2 production, increase cell proliferation, and prevent GC apoptosis [ 135 ].

The synthesis of steroid hormones in GCs can also be influenced by non-granulosa cell-derived ncRNAs. The long noncoding RNA LIPE-AS1, which is prevalent in follicular fluid exosomes, is a prominent example. Within GCs, this lncRNA functions as a molecular sponge for miR-4306, reducing its inhibitory effects. This results in increased synthesis of estrogen (E2) by upregulating the expression of important steroidogenic genes, such as CYP11A1, CYP17A1, and steroidogenic acute regulatory protein (StAR). According to research employing KGN cell models, this molecular action promotes GC proliferation, lowers programmed cell death, and aids in the healthy development and maturation of oocytes [ 130 ]. Similarly, miR-21, which inhibits the expression of the tumor suppressor gene LATS1 in granulosa cells GCs, is transported by exosomes produced from human umbilical cord mesenchymal stem cells (hucMSCs). In the end, this inhibition increases the synthesis of estrogen by lowering the levels of the transcriptional regulator YAP and phosphorylating LOXL2 [ 136 ]. Additionally, unique miRNA profiles seen in exosomes extracted from the plasma of people with PCOS have a complex impact on granulosa cell (GC) behavior and steroid hormone synthesis. For example, higher levels of miR-18a-3p, miR-20b-5p, and miR-106a-5p are linked to a significant decrease in the production of estradiol (E2). Notably, progesterone synthesis is likewise stimulated by miR-106a-5p. On the other hand, overexpression of miR-126-3p and miR-146a-5p reduces progesterone production and GC proliferation while increasing estradiol output [ 137 ].

Mitochondrial activity is crucial for GC function and follicular development [ 138 ], and ovarian dysfunction is linked to abnormalities in mitochondrial activity [ 139 , 140 ]. Recent studies have revealed how non-coding RNAs modify mitochondrial activity to carefully regulate important granulosa cell functions, including proliferation and programmed cell death. One such example is miR-484, which plays a key role in controlling the division and unification of mitochondria [ 141 ]. Elevated levels of miR-484 in granulosa cells have been demonstrated to enhance mitochondrial fragmentation, induce loss of mitochondrial membrane potential, and trigger mitochondria-mediated apoptosis [ 142 ]. According to more research, linc00958 competes with miR-484 as an endogenous RNA (ceRNA) and forms a regulatory pathway involving Sestrin2 (SESN2) in the presence of oxidative stress. In granulosa cells, the linc00958/miR-484/SESN2 axis regulates apoptotic events linked to mitochondria and mitochondrial dysfunction [ 142 ]. In granulosa cells, miR-484 specifically targets YAP1 mRNA, resulting in mitochondrial dysfunction marked by decreased ATP synthesis, increased mitochondrial membrane potential (MMP) depolarization, and decreased reactive oxygen species (ROS) clearance. All of these consequences lead to apoptosis and a reduction in granulosa cell viability [ 143 ]. Increased mitochondrial membrane potential (MMP), enhanced cell survival, and reduced apoptosis are all correlated with higher levels of miR-96-5p in KGN cells. This suggests that miR-96-5p stimulates granulosa cell proliferation and inhibits apoptosis via modifying the mitochondrial apoptotic pathway [ 135 ]. On the other hand, granulosa cells that overexpress lnc-CCNL1-3:1 produce more ROS, less ATP, and compromised mitochondrial activity, which eventually leads to death [ 144 ]. In the early phases of GC apoptosis, lncRNA MEG3 can be silenced to repair MMP and decrease the production of apoptotic proteins, improving cell survival and lowering apoptosis [ 145 ].

While there is still much to learn about how ncRNAs control mitochondrial activity in granulosa cells, preliminary research offers promising hints. For instance, the regulation of mitochondrial proteins and biogenesis has been connected to miRNAs, including miR-125b-5p, miR-132-3p, miR-19a-3p, miR-30a-5p, and miR-660-5p, which exhibit changed expression levels in the follicular fluid of women with reduced ovarian reserve. These discoveries pave the way for further research into the ways ncRNAs affect granulosa cell mitochondrial function, which may provide fresh insights into ovarian health and associated conditions.

Testicular hormone regulation

To sustain Sox9 expression and encourage testis growth, the lncRNA TESCO binds to the transcription factor SF1 [ 146 , 147 ]. By suppressing Dmrt1 expression, the lncRNA DMR contributes to sexual differentiation [ 148 ]. The covalently closed-loop structure of circRNAs is distinguished by the absence of terminal 5′ caps and 3′ polyadenylated tails [ 149 , 150 ]. By capturing miRNAs and stopping them from attaching to their target mRNAs, they act as miRNA sponges, controlling gene expression [ 151 ]. The function of circRNAs in teleost sex differentiation, however, has been the subject of very few investigations.

Some of the most extensively researched smaRNAs are miRNAs, which are conserved among species [ 23 , 152 ]. The most prevalent sequences, according to an analysis of the smaRNA length distribution, are those with 26–29 nucleotides. PiRNAs, a subtype of smaRNAs with 25–30 nucleotides that are mostly expressed in germ cells and crucial for germline development, are probably highly expressed, which accounts for this preponderance [ 153 ]. Our results are consistent with earlier studies on tilapia (Oreochromis niloticus) and zebrafish (Danio rerio), indicating the conserved function of smaRNAs, especially piRNAs, in germline development in these species [ 154 , 155 ].

Male infertility

This subsection critically evaluates ncRNA evidence in male infertility, emphasizing study design, assay reproducibility, linkage to clinical endpoints (fertilization, early cleavage, blastulation, live birth), and direct comparisons with female infertility data.

Among male-side ncRNAs, miR-34c in sperm and seminal plasma shows the strongest association with fertilization and early cleavage competence. PIWI–piRNA pathway defects map mechanistically to meiotic arrest and non-obstructive azoospermia (NOA), with tissue-level confirmation from human testicular studies. tRFs/tsRNAs correlate with sperm motility and early embryo programming and are supported by both human association and animal mechanistic data. Sperm-enriched circRNAs are emerging as potential regulators of spermatogenesis and motility but remain at an exploratory stage with limited clinical endpoint data [ 156 ]. Overall, most male studies link ncRNA expression to semen parameters or embryology laboratory outcomes, while prospective validation against live-birth endpoints is still rare compared with female cohorts.

Evidence is constrained by (1) small, single-center cohorts; (2) assay heterogeneity (qRT-PCR versus small-RNA sequencing and inconsistent normalization); (3) phenotype misclassification (for example, OAT versus idiopathic infertility); and (4) reliance on laboratory measures rather than pregnancy or live-birth outcomes. Standardizing pre-analytical handling, establishing reference ranges, and applying robust statistical adjustments (for age, abstinence period, BMI, varicocele, and smoking) are essential next steps for clinical translation [ 157 ].

Major research gaps include the absence of large, prospective, multi-center cohorts with live-birth endpoints; limited external validation and blinding; inconsistent normalization across analytical platforms; and a lack of decision-curve analyses to demonstrate added value beyond standard WHO semen parameters. Moving forward, prospective registries should be launched, standard operating procedures harmonized, external RNA standards (e.g., ERCC) adopted, and incremental predictive value (AUC or net benefit) reported relative to existing clinical models [ 158 ].

Taken together, these observations place miR-34c at a medium-to-high level of translational readiness because of its reproducible association with fertilization and early cleavage in human IVF/ICSI cohorts. PIWI–piRNA pathway markers reach a moderate level, with strong mechanistic support but limited prospective validation. tRFs/tsRNAs occupy a medium tier, reflecting solid mechanistic backing but fewer independent cohorts. Sperm circRNAs remain low-to-medium, given their discovery-stage evidence base [ 159 ].

Female-side ncRNA biomarkers (e.g., serum or follicular-fluid panels in PCOS, endometrial/circulating panels in endometriosis and recurrent implantation failure) benefit from larger cohorts, clearer procedural sampling windows, and more prospective validation. Male-side studies are richer in mechanistic tissue evidence, such as PIWI–piRNA dysfunction in the testis, but leaner in clinical endpoint linkage and multi-center validation. Consequently, female pipelines appear closer to diagnostic deployment, whereas male pipelines require standardization and prospective outcome studies to reach parity [ 160 – 162 ]. Table 1 provides a concise overview of the principal non-coding RNA classes, summarizing their structures, reproductive functions, representative mechanisms, and robust detection strategies. Collectively, these mechanistic insights motivate a direct mapping from ncRNA pathways to specific clinical infertility phenotypes and their diagnostic or therapeutic implications. Table 1 Multifaceted NcRNA landscape shaping reproductive biology, experimental validation, and therapeutic frontiers ncRNA Size Core Role Male Impact Female Impact Experimental Conclusion Key Detection References MicroRNAs (miRNAs) ~ 19–25 nt Post-transcriptional silencing; SSC renewal Controls SSC viability/differentiation Regulates folliculogenesis, oocyte meiosis miR-21 loss → germ-cell apoptosis; miR-146 ↑ SSC differentiation qRT-PCR, small-RNA-seq [ 14 , 163 ] Piwi-interacting RNAs (piRNAs) ~ 24–31 nt Transposon silencing; genome stability Essential for spermatogenesis Linked to oocyte quality PIWI loss blocks spermatogenesis, destabilizes germline DNA PIWI-IP RNA-seq [ 164 – 167 ] Long Noncoding RNAs (lncRNAs) >200 nt Epigenetic regulation, X-inactivation Drives SSC self-renewal Controls imprinting; Xist is needed for embryo survival Xist deletion → female embryonic lethality; AK015322 ↑ SSC proliferation RNA-seq, RNAscope [ 168 ] Small Nucleolar RNAs (snoRNAs) 60–300 nt rRNA processing/modification Supports ribosome biogenesis Required for oocyte maturation Depletion → faulty ribosome assembly, reduced fertility Northern blot, RT-PCR [ 169 – 171 ] Small interfering RNAs (siRNAs) ~ 21 nt RNA interference, antiviral defense Stabilizes testicular transcripts Critical for oogenesis/early embryo Dicer knockout disrupts meiosis and embryo development Small-RNA-seq [ 172 , 173 ] Circular RNAs (circRNAs) Variable loop miRNA sponge; transcription control Maintains SSC function Influences implantation/embryo development Stage-specific expression enhances SSC viability RNase-R RNA-seq [ 174 ] Small Nuclear RNAs (snRNAs) 100–300 nt Pre-mRNA splicing Required for spermatogenesis Required for oocyte maturation Defects impair gametogenesis and embryo development RNA-seq, IP-RT-PCR [ 175 , 176 ] tRNA-derived Fragments (tRFs/tsRNAs) 15–40 nt Translation control; embryo gene regulation Shapes sperm RNA cargo; epigenetic inheritance Affects cleavage and implantation Altered profiles associate with infertility and intergenerational inheritance tRF-specific qRT-PCR [ 177 ]

Clinical implications of NcRNA dysregulation in infertility

Emerging translational research demonstrates that specific ncRNAs act as molecular “fingerprints” of infertility, detectable in easily obtained clinical specimens such as seminal plasma, spermatozoa, follicular fluid, granulosa cells, endometrium, and circulating extracellular vesicles. Multi-omic profiling now confirms that consistent expression shifts in these ncRNAs accompany distinct infertility phenotypes, including NOA, oligo-astheno-teratozoospermia (OAT), polycystic ovary syndrome (PCOS), endometriosis-associated infertility, and recurrent implantation failure (RIF) [ 160 , 178 ].

Unlike earlier descriptive reports, recent studies integrate mechanistic pathway analysis with patient-level outcomes, showing that many ncRNAs both drive pathophysiology and provide measurable biomarkers. For example, dysregulated microRNAs alter granulosa-cell steroidogenesis and endometrial receptivity; aberrant piRNA pathway components compromise genomic integrity during spermatogenesis; and lncRNAs such as H19 and MEG3 disrupt epigenetic imprinting critical for implantation. These findings open dual clinical opportunities:

Diagnostics/Prognostics: stable, minimally invasive readouts from serum or follicular-fluid exosomes for early detection, risk stratification, or in-vitro fertilization (IVF) outcome prediction. Therapeutics: precision interventions such as miRNA mimics or antagomirs, lncRNA knockdown, or circRNA decoys designed to restore normal gene-regulatory networks in the ovary or testis [ 179 , 180 ].

Table 2 distills these advances by mapping each major ncRNA class to its verified infertility phenotype, specimen type, and demonstrated or potential clinical utility, offering a concise translational framework that links molecular pathways to real-world diagnostic and therapeutic strategies [ 181 , 182 ]. Table 2 Emerging NcRNA signatures revolutionize infertility diagnostics, prognosis, and therapeutics ncRNA/Axis Specimen & Assay Key Dysregulation/Mechanistic Note Clinical Infertility Phenotype Clinical Utility Evidence References miR-21 Follicular fluid/granulosa cells (qRT-PCR, EV-miRNA) Alters granulosa steroidogenesis and viability when dysregulated Polycystic ovary syndrome (PCOS) Candidate serum/follicular biomarker; experimental antagomir studies Human case–control & pre-clinical [ 183 ] miR-34c Sperm/seminal plasma (qRT-PCR) Reduced levels hinder the first zygotic cleavage and early embryo development. Male factor infertility (OAT, fertilization failure) Seminal marker predicting fertilization and cleavage competence Human IVF/ICSI cohorts [ 156 ] Circulating miRNAs (miR-200c-3p, miR-17-5p, miR-451a) Endometrium/serum (qRT-PCR, EV-miRNA) Disrupt implantation and inflammatory pathways Endometriosis-associated infertility Non-invasive serum or endometrial biomarker panels Human case–control & meta-analyses [ 184 ] PIWI–piRNA pathway (PIWIL1/2, MILI/MIWI) Testicular tissue (RNA-seq, IHC) piRNA deficiency activates transposons and causes meiotic arrest Non-obstructive azoospermia (NOA) Genetic screening guides micro-TESE retrieval Human tissue sequencing & functional studies [ 185 ] lncRNA H19 Endometrium/serum/EVs (qRT-PCR) Down-regulated in RIF; dysregulated in PCOS, affects imprinting and receptivity Recurrent implantation failure (RIF); PCOS Biomarker candidate; potential therapeutic target Human cohorts & meta-analyses [ 186 , 187 ] Testis-enriched circRNAs Sperm/testis (RNase-R RNA-seq; divergent qPCR) miRNA sponges regulating spermatogenesis and sperm motility Male factor infertility (motility/SSC maintenance) Exploratory sperm circRNA diagnostic panels Small human cohorts, discovery stage [ 188 ] tRFs/tsRNAs Sperm (small-RNA-seq) Altered sperm tRF payload modifies early embryo gene expression and mediates intergenerational inheritance. Male factor infertility; recurrent early pregnancy loss Risk stratification; embryo-quality assessment research Human association + animal mechanistic studies [ 189 ] miR-93/miR-132/miR-99a Follicular fluid/granulosa cells (qRT-PCR) Dysregulated profiles affect ovarian response and granulosa proliferation Poor ovarian response; PCOS Follicular-fluid miRNA panels predicting oocyte/embryo quality Human IVF cohorts [ 190 , 191 ]

Mechanisms of noncoding RNAs in infertility

MicroRNAs (miRNAs) in infertility

Mechanism: Post-transcriptional regulation of fertility-related genes

Clarifying the processes by which lncRNAs alter gene expression in SSCs is crucial for comprehending the intricate regulatory networks at play in an academic setting. This covers their functions in transcriptional control, post-transcriptional regulation, and chromatin remodeling.

Gene accessibility for transcription is determined by the condensed or open configurations of chromatin, a DNA-protein complex. LncRNAs are important chromatin architectural regulators in SSCs, which affect gene expression. By attaching to proteins like as DNA methyltransferases and histone-modifying enzymes, they route epigenetic modifiers to certain genomic loci, changing chromatin states and controlling transcriptional activity. These epigenetic proteins are guided by lncRNAs to specific genomic sites where they alter DNA and histones by adding or removing chemical markers. Gene expression is regulated by these changes, which affect whether genes are in an active, transcription-friendly state or a silent, repressive state [ 192 ].

To bring these regulatory components closer together, certain lncRNAs encourage physical looping between distant enhancers and gene promoters. By enabling enhancers to efficiently activate their target genes, this spatial arrangement raises the likelihood of gene activation. This process allows lncRNAs to alter the expression of genes essential for SSC differentiation and self-renewal [ 193 ].

Protein synthesis is made possible by transcription, which transforms genetic instructions from DNA into RNA. To fine-tune gene expression patterns crucial for SSC function, lncRNAs in SSCs control transcription in a variety of ways, including by interacting with transcription factors, enlisting chromatin remodelers, or serving as scaffolds to construct transcriptional machinery. By aiding in the recruitment and binding of transcription factors and RNA polymerase to gene promoters, several lncRNAs serve as transcriptional enhancers. Target gene mRNA synthesis is increased as a result of this activity, which also increases the initiation and elongation stages of transcription. These lncRNAs encourage the expression of genes essential for differentiation, proliferation, and self-renewal in SSCs [ 194 ].

On the other hand, certain lncRNAs function as transcriptional repressors by blocking the binding or recruitment of transcription factors and RNA polymerase to gene promoters. Certain genes have decreased expression as a result of this interference, which inhibits the start of transcription. Through the silence of genes that must be switched off in specific developmental or environmental settings, such lncRNAs aid in the maintenance of cellular identity inside SSCs [ 195 ].

The regulatory processes that occur after an RNA molecule is produced but before it is translated into a protein are known as post-transcriptional changes. RNA stability, splicing, transport, and translation efficiency are all modulated by LncRNAs, which help to fine-tune gene expression in SSCs [ 196 ].

LncRNAs can attach to pre-mRNAs and change their splicing choices, affecting whether exons are included or left out. Multiple mRNA variants are produced from a single gene as a result of this alternative splicing, which eventually diversifies the protein products in SSCs. By this process, lncRNAs contribute to the formation of the functional protein landscape that is essential for the maintenance and differentiation of SSCs.

Overall, lncRNAs in SSCs play a variety of roles in gene regulation, coordinating chromatin architecture, transcriptional activity, and post-transcriptional processes to ensure precise control of gene expression. RNA Stability and Translation: LncRNAs can bind to mRNAs to modulate their stability and control how efficiently they are translated into proteins. By influencing mRNA degradation rates or enhancing/inhibiting their translation, lncRNAs fine-tune the levels of important proteins required for SSC function [ 195 ]. Their ability to alter these vital regulatory networks emphasizes how important lncRNAs are in coordinating the particular gene expression programs needed for spermatogenesis, differentiation, and SSC self-renewal. Deciphering the intricacies of male reproductive biology requires a thorough grasp of these pathways, which also holds promise for the development of focused treatments to address male fertility problems and enhance reproductive health.

MiRNA involvement in spermatogenesis, oocyte development, and implantation

The role of MiRNAs in male gametogenesis

The creation of early spermatocytes, the production of haploid round spermatids, the mitotic division and proliferation of spermatogonia, chromatin condensation, and nuclear sculpting are all important steps in the complex process of spermatogenesis. In order to produce mature, functioning spermatozoa, this procedure also involves the removal of excess cytoplasm and the development of the acrosome and sperm tail [ 197 , 198 ]. Spermatogenesis is the process by which a single spermatocyte divides into four viable, equal-sized spermatids. To ensure the effective creation of mature sperm, some genes are triggered throughout this process to support the growth and multiplication of spermatogenic cells [ 199 ]. Male gametogenesis does, in fact, include the dynamic expression of many non-coding genes, such as miRNAs, which are essential regulators of the process, in addition to the phase-specific activation of protein-coding genes [ 197 , 200 ]. In this regard, miRNAs’ existence in canine testing [ 199 ], Testicles from mice and mice have been found [ 201 , 202 ]. Further evidence of the conserved gonad-specific miRNAs’ possible role in testicular development comes from the increased expression of these miRNAs in the testis’s Sertoli cells, including miR-202-5p and miR-202-3p [ 203 ].

In fact, research employing DICER and Drosha knockout animals has shown that miRNAs are actively biosynthesised during spermatogenesis, similar to what is seen in oocytes. Comparing the sperm from these knockout animals to wild-type controls using small non-coding RNA sequencing showed that between 47% and 52% of the miRNAs seen in wild-type sperm were dysregulated in the knockout groups. This discovery clearly suggests that miRNA transcription is continuous and crucial during spermatogenesis [ 204 ]. The pathophysiology of male infertility and the crucial role of miRNAs in spermatogenesis have been clarified by thorough examinations of miRNA expression profiles in spermatozoa derived from prepubertally hemicastrated Yorkshire, Landrace, and Duroc boars [ 205 , 206 ]. On the other hand, male infertility and poor sperm quality have been linked to dysregulated expression of certain miRNAs. Notably, in spermatozoa, the expression profiles of miR-15a, miR-29b, miR-10a, miR-34a, miR-34b, and miR-34c have been linked to fertility status in a variety of species, including mice, cattle, and humans [ 207 – 213 ]. Further research has also demonstrated how different miRNAs may influence spermatogenesis by controlling Sertoli cell activity. As vital somatic cells, Sertoli cells are important for both the spermatogenic process and testicular growth [ 210 ]. For example, miR-1285 and miR-762 have been demonstrated to increase the activity of porcine Sertoli cells by altering the expression of the ring finger protein 4 (RNF4) gene [ 211 ]. Similar to this, miR-638 has a role in spermatogenesis in pigs by controlling the growth and death of immature Sertoli cells by specifically altering the expression of the sperm-associated antigen 1 (SPAG1) gene [ 212 ].

The role of cellular MiRNAs in follicular development and oocyte maturation

Different gene expression levels within granulosa cells, theca cells, and oocytes define the production of fertilizable ova, which is controlled by the complex ovarian-uterine-pituitary paracrine and endocrine communication networks [ 80 , 81 , 214 ]. In this regard, transcriptome investigations have shown that genes linked to cell proliferation are significantly upregulated in dominant follicles, whereas genes linked to cell death and apoptosis are mostly expressed in subordinate follicles [ 80 , 81 , 214 , 215 ].

Functional deletion of the DICER1 gene has demonstrated the involvement of miRNAs in oogenesis [ 216 ]. An essential part of the RNA-induced silencing complex (RISC), which is part of the machinery that processes miRNA, is argonaute 2 (AGO2) [ 217 ], and the gene Drosha, which is in charge of digesting Pri-miRNA [ 218 ]. The crucial role that miRNA biogenesis plays in ovarian function and gametogenesis progression has been confirmed by several functional investigations. To further clarify the basic processes of miRNA-mediated post-transcriptional gene regulation during oogenesis, a great deal of research has been done on miRNA expression and function. The expression patterns of miRNAs in bovine cumulus–oocyte complexes have been well described in this regard [ 219 ], tissue from the bovine corpus luteum [ 220 ] and the ovarian cortex of an adult cow [ 86 ], embryos, bovine follicular fluid, and cow fetal ovaries [ 111 , 112 , 221 , 222 ], It is also widely known that bovine granulosa cells express miRNAs [ 213 , 223 ]. Therefore, to clarify the post-transcriptional regulatory mechanisms controlling folliculogenesis and oogenesis, a thorough grasp of the basic functions of miRNAs within ovarian physiology, specifically across distinct follicular compartments including oocytes, theca cells, granulosa cells, and follicular fluid, across various stages of the female reproductive cycle, is necessary. Furthermore, examining the miRNA expression patterns of healthy vs. atretic follicles, as well as follicles of different sizes (dominant versus subordinate), may offer important new information on the miRNAs that are essential for ovulation and follicular development. Accordingly, prior research has shown that miRNAs involved in follicular cell proliferation, steroidogenesis, luteinization, and oocyte maturation are expressed differently in small vs. big follicles and in healthy versus atretic bovine follicles [ 90 , 223 , 224 ]. Furthermore, at various phases of the bovine estrous cycle, diverse patterns of miRNA expression have been noted in small and big follicles. Day 3 showed differential regulation of miRNAs linked to pathways such as apoptosis, transforming growth factor-beta (TGF-β) signaling, axon guidance, and Wnt signaling. The metabolic pathways involving vitamins, cofactors, lipids, lipoproteins, and sulfur-containing amino acids such as cysteine and methionine were the main targets of the miRNAs that showed differential expression by day 7 [ 223 ]. These findings show that miRNAs may play a substantial role in follicular recruitment and selection during the earliest follicular waves in cattle. Moreover, understanding miRNA expression levels during the follicular phase of the estrous cycle might give useful insights into miRNAs directly engaged in the ovulatory process. Accordingly, on day 19 of the bovine estrous cycle, our earlier study showed that granulosa cells of preovulatory dominant and subordinate follicles significantly differed in their expression of miRNAs linked to cell adhesion, cell proliferation, apoptosis, and metabolic pathways [ 90 ]. Similar to this, it is known that LH may cause oocytes in mid- to late vitellogenic follicles to develop, but tiny early vitellogenic follicles are incapable of doing so. In this regard, follicular cells from early and mid-to late vitellogenic stage follicles were discovered to express several miRNAs at high levels. However, follicles unable to advance to oocyte maturation showed clearly different expression patterns of 24 unique miRNAs, including miR-22a-3p, miR-16a, miR-181a-3p, and miR-29a [ 225 ].

Determining the miRNA expression patterns in animals like cattle during the luteal and follicular stages of the reproductive cycle provides important information on the post-transcriptional regulatory mechanisms that control oocyte ovulation and follicular atresia [ 90 , 223 ]. On the other hand, these studies could make it easier to identify the miRNAs that control steroidogenesis, which is necessary for folliculogenesis to proceed correctly [ 103 , 226 – 229 ]. However, follicular development may be negatively impacted by dysregulated expression of developmentally essential miRNAs throughout critical stages of the reproductive cycle, which may result in anovulation or the ovulation of non-viable eggs. In one study, overexpression of miR-378 in the mouse ovarian bursa led to a decrease in ovarian size and pups, illustrating this phenomenon [ 230 ].

The process of oocyte production during mammalian oogenesis is distinguished by the simultaneous advancement of nuclear and cytoplasmic maturation. Numerous studies have shown that a significant increase in transcripts and proteins also characterizes this embryonic stage. Significant variations in microRNA expression patterns have been noted in tandem with these biochemical and morphological changes, which differentiate immature oocytes from their fully mature counterparts. These variations in microRNA dynamics point to a crucial regulatory function in the control of gene expression during the maturation of the oocyte [ 219 , 231 , 232 ]. For instance, microRNA expression dynamically varies in pig oocytes as they go from the germinal vesicle (GV) stage to the metaphase II (MII) stage. In particular, throughout this maturation phase, there is a notable upregulation of miR-486, miR-10b, miR-10a-5p, miR-183, and miR-21, whereas there is a notable downregulation of miR-210 and miR-27b-3p expression. These changes in expression highlight the possible role of certain microRNAs in controlling the molecular processes that underlie oocyte maturation [ 233 ]. Different phases of maturation in bovine oocytes have been found to exhibit diverse microRNA expression patterns, suggesting regulatory responsibilities particular to each stage. Notably, oocytes at the GV stage were the only time when thirty microRNAs, including miR-208a, miR-2317, miR-2320, miR-365-5p, miR-584, miR-628, and miR-876, were expressed. On the other hand, 35 microRNAs were identified in oocytes at the MII stage, including miR-144, miR-1603, miR-190b, miR-29b, miR-29c, miR-29e, miR-412, and miR-449b. Different sets of microRNAs may play a role in regulating gene expression programs essential for oocyte maturation and developmental competence, according to these stage-specific expression patterns [ 231 ]. Similarly [ 219 ], Numerous microRNAs, including miR-130b, have been shown in many studies to express differently in bovine oocytes during the GV and MII phases. Notably, miR-130b has a crucial role in increasing oocyte maturation, according to functional investigations carried out in vitro. The modification of important target genes like SMAD5 and MSK1, which are both involved in signaling pathways crucial for the embryonic advancement of oocytes, mediates this regulatory role, at least in part. These results highlight the functional significance of certain microRNAs in coordinating the molecular processes underlying oocyte maturation [ 234 ]. The functional role of many other microRNAs in the control of oogenesis has also been emphasized by other research. It has been demonstrated that several microRNAs, including miR-318, miR-202, let-7 family members, miR-278, miR-378, and miR-125a-3p, are involved in important facets of oocyte growth and maturation. It is thought that these microRNAs act by modifying gene expression networks that control cytoplasmic remodeling, folliculogenesis, and cell cycle regulation. All of these results support the idea that microRNAs are essential for coordinating the intricate molecular processes that underlie mammalian oogenesis [ 235 – 239 ].

Functional analysis of MiRNAs in oocyte companion somatic cells

The majority of functional investigations depend on in vitro research utilizing granulosa and cumulus cells, since it is challenging to directly manipulate miRNA levels in oocytes. Through signaling pathways, these support cells affect oocyte maturation. They may also use extracellular vesicles to deliver miRNAs to the oocyte. Therefore, many miRNAs have an indirect effect on oogenesis by controlling the survival and proliferation of these companion cells, or they have a direct effect by altering the expression of genes in oocytes, particularly during critical transitions like the dissolution of germinal vesicles and the advancement to the MII stage. For instance, it has been demonstrated that increased expression of miR-378 in pig cumulus cells inhibits cumulus cell growth and prevents oocytes in the GV stage from progressing to the MII stage. The downregulation of important genes involved in cumulus cell growth mediates this impact, underscoring the critical function of miR-378 in regulating the cellular milieu required for oocyte maturation [ 239 ]. Similarly, it has been demonstrated that increased levels of miR-224 and miR-574 in porcine cumulus cells during in vitro oocyte maturation reduce the percentage of oocytes in the GV stage that make it to the MII stage, suggesting that these molecules have an inhibitory function in oocyte developmental competence [ 240 ].

Beyond these instances, a number of in vitro functional investigations have shown that microRNAs predominantly affect oocyte maturation by altering the activity of granulosa and cumulus cells. For example, one study found that miR-130b supports the microenvironment required for oocyte development by increasing the survival and proliferation of granulosa and cumulus cells, which in turn improves oocyte maturation [ 234 ]. Similarly, microRNAs like miR-375 can affect oocyte maturation by targeting important genes like ADAM metallopeptidase with thrombospondin type 1 motif 1* (ADAMTS1) and progesterone receptor (PGR), as shown by overexpression and knockdown studies using lentiviral transduction in bovine cumulus cells. These results demonstrate how miR-375 regulates the expression of genes essential for cumulus cell activity and oocyte developmental competence [ 241 ]. Furthermore, it has been shown that miR-21-3p inhibits autophagy, a process that affects the destiny of granulosa cells, in bovine granulosa cells. Targeting VEGFA and modifying the PI3K/AKT signaling pathway, this regulation highlights the crucial role that miR-21-3p plays in regulating the survival and function of granulosa cells during folliculogenesis [ 242 ]. Furthermore, a number of microRNAs, including miR-146a, the miR-183-96-182 cluster, miR-383, and others, have been demonstrated through in vitro functional investigations to be crucial in controlling folliculogenesis and oocyte maturation. It is believed that the main way in which these miRNAs aid in these processes is by encouraging the survival and growth of cumulus and granulosa cells, which creates an environment that is favorable for oocyte development Fig. 1 . Fig. 1 ncRNA regulation in oogenesis and spermatogenesis. Key noncoding RNAs modulate oocyte and sperm development by controlling cell growth, meiosis, and maturation essential for fertility

The role of extracellular Vesicles-Mediated MiRNAs in female gametogenesis

The intricate biological process of oogenesis involves a great deal of cell-to-cell contact between the oocyte and the somatic cells that surround it in the follicular milieu. A network of gap junctions and several other systems, including paracrine, autocrine, and endocrine signaling pathways, enable this bidirectional contact. These mechanisms work together to coordinate the molecular and cellular processes necessary for oocyte development and maturation [ 198 , 243 ]. Cell-to-cell interactions within the follicular milieu have taken on a new dimension with the discovery of extracellular vesicles (EVs), in addition to these well-established communication channels. Microvesicles that transport both proteins and microRNAs have been found in equine follicular fluid. Interestingly, some of these microRNAs are also present in the granulosa and cumulus cells that surround them. This suggests that microvesicles and exosomes play a critical role in regulating follicular growth and oocyte maturation by facilitating the movement of bioactive chemicals across cells [ 244 ]. The existence of miRNAs in bovine extracellular vesicles [ 222 , 245 ]. The possible functions of extracellular vesicle (EV)-mediated microRNAs in controlling folliculogenesis have been brought to light by investigations of human and pig follicular fluids. These results imply that EVs are significant miRNA carriers, promoting intercellular communication that affects follicle growth and development [ 246 , 247 ]. Follicle size and/or reproductive cycles influence the EV-mediated miRNAs’ expression patterns [ 248 , 249 ]. For instance, it has been discovered that extracellular vesicles extracted from human follicular fluid obtained during ovulation contain microRNAs linked to the control of cellular meiosis, such as miR-132, miR-212, and miR-214, as well as microRNAs predicted to be involved in follicle development, such as miR-99a, miR-100, miR-132, and miR-218. These results highlight how important EV-mediated miRNA transfer is for coordinating important activities during oocyte maturation and folliculogenesis [ 248 ]. Additionally, the roles of extracellular vesicle-mediated microRNAs in female gametogenesis are supported by both experimentally confirmed and hypothesized data. The follicular fluid of women whose oocytes failed to fertilize, for instance, had higher levels of exosome-derived miR-92a and miR-130b, indicating that these miRNAs may have a detrimental effect on oocyte quality and fertilization potential [ 250 ]. This suggests that, in addition to autocrine and paracrine signaling, microRNAs transported by extracellular vesicles in follicular fluid function as extra regulators of stage-specific follicular growth and oocyte maturation. Additionally, there is evidence that stressors like oxidative stress or hormonal fluctuations may enhance the production of these vesicles during folliculogenesis. Through the transmission of crucial regulatory molecules within the follicular milieu, this stress-induced Follicle function adaptability and maintenance may be facilitated by vesicle release. For instance, research [ 252 ] showed that follicular fluid-derived exosomes enhance oocyte function by preventing stress during in vitro maturation. Exosomes, microvesicles, apoptotic bodies, and necrotic debris are examples of extracellular vesicles that are thought to be released into the extracellular space in response to cellular stress. By distributing bioactive compounds that promote the survival and functionality of nearby cells, these vesicles work together to play a protective role. Cumulus-oocyte complexes (COCs) and extracellular vesicles EVs extracted from the follicular fluid of heat-stressed cows were co-cultured in a study to better clarify these phenomena. The expression levels of important genes in cumulus cells, such as IGFBP2, BMP15, GDF9, HAS2, and STAT3, were noticeably greater in COCs treated with heat stress-derived EVs than in those exposed to EVs from cows kept in thermo-neutral circumstances. According to these results, EVs generated under stress may contain chemical cues that improve cellular reactions meant to safeguard and promote oocyte development in the face of environmental stressors [ 251 ].

The role of MiRNAs during preimplantation mammalian embryo development

Before implantation in the intricate process of mammalian embryogenesis, the fertilized egg goes through many cleavage divisions to create an embryo that can be implanted. The breakdown of maternal RNA and proteins, the start of minor and major embryonic genome activation, embryonic compaction, the creation of the blastocoel cavity, and the differentiation of cells into the inner cell mass and the outer epithelial trophectoderm are the characteristics of this early stage of embryonic development [ 252 ]. There is evidence that many genes express themselves differently depending on the stage at which these crucial early developmental events occur. The tightly controlled genetic control underlying embryonic development is demonstrated by the fact that, for instance, 717 genes show increased expression during mouse embryogenesis as the embryo moves from the 2- to 4-cell stage, 831 genes are upregulated from the 4- to 8-cell stage, and 839 genes show elevated expression during the transition from compaction to the morula stage [ 253 ]. Similar stage-specific gene expression patterns have been found in bovine preimplantation embryos, where the inner cell mass and trophectoderm of the blastocyst exhibit differential expression of over 870 genes, including important regulators like NANOG, SOX2, STAT3, ELF5, GATA3, and KRT18. These results demonstrate how the transcriptome modifications during early mammalian development are dynamic and strictly controlled [ 254 , 255 ]. However, aberrant embryonic development or early embryonic loss may result from dysregulation of these developmentally important genes at any point throughout early embryogenesis. The significance of precise gene regulation for successful embryo development and implantation is highlighted by the fact that implantation-incompetent dormant mouse blastocysts show altered expression of genes involved in important processes like cell cycle regulation, cell signaling, and energy metabolism [ 256 ]. Furthermore, defective or incompetent embryo development has been associated with altered expression of genes such as B3GNT5, EOMES, and WNT3A in human blastocysts and KRT8, PGK1, AKR1B1, EEF1A1, MSX1, and PTTG1 in bovine blastocysts. Early embryogenesis may experience developmental halt or failure as a result of these gene expression alterations that impair vital cellular processes [ 257 , 258 ]. Together, these and other studies show that dynamic, stage-specific expression of genes and their products characterizes preimplantation embryo development. The exact processes that cause the overexpression or downregulation of particular genes at various embryonic stages, however, are still mostly unknown and need more research.

The stage-specific functions of miRNAs during early mammalian embryogenesis have attracted more attention, much like those of protein-coding genes. Studies demonstrating that deletion of important miRNA processing genes, such as DICER and AGO2, causes embryonic arrest around embryonic day 6.5 (E6.5) or embryonic lethality during gastrulation provided the first evidence of the significance of miRNAs in embryonic development. These findings underscored the critical role of miRNA-mediated regulation in early development [ 259 , 260 ]. Thus, by controlling the quantity of certain proteins or enzymes, either via mRNA degradation or translation inhibition, miRNAs may influence embryonic development. Both functional investigations and thorough miRNA profiling analyses have provided evidence for the role of miRNAs in important preimplantation processes, including the maternal-to-zygotic transition, embryonic compaction, and blastocyst development. Between the zygote and 2-cell stages of mouse embryogenesis, maternally derived miRNAs are globally degraded. From the 2-cell stage onward, a wide variety of miRNAs are synthesized from scratch. The shift from maternal to embryonic regulation of development is supported by a closely controlled change in the short RNA landscape, which is reflected in this dynamic turnover [ 261 ], reduced number of hatched and unbroken blastocysts and elevated expression of Let-7a till the 8-cell stage [ 262 ], higher levels of miR-130a and miR-21 expression in zygotes compared to 8-cell stage embryos [ 263 ], In bovine embryos, elevated expression of several microRNAs, such as miR-205, miR-150, miR-96, miR-122, miR-146a, miR-145, miR-208, and miR-496, coincides with the minor and major embryonic genome activation. This increase implies that these miRNAs have significant regulatory functions throughout the early stages of embryonic development and during the activation of the genome [ 219 , 221 ], Early bovine blastocysts showed increased expression of miR-135a, miR-218, miR-335, and miR-449b in comparison to hatched ones [ 264 ], The mouse embryo’s dynamic and strictly controlled expression patterns of miRNAs throughout preimplantation development are best shown by the downregulation of miR-182 between the 2- and 4-cell stages and the subsequent increase between the 4- and 8-cell stages. Furthermore, these variations draw attention to the possible functions of certain miRNAs in coordinating crucial cellular functions and developmental changes in the early stages of embryonic development [ 265 ], Studies conducted on mice and zebrafish have shown that certain miRNAs, such as those in the let-7 family, are inherited from the mother but seem to be unnecessary for the early stages of embryonic development. This implies that although the maternal contribution contributes these miRNAs, their role may not be crucial in the early phases of embryogenesis [ 261 , 266 ]. This demonstrates how miRNA expression is precisely regulated and stage-specific during the early stages of embryonic development. It is crucial to remember that whereas many miRNAs exhibit dynamic alterations to control developmental transitions, others exhibit little to no stage-to-stage fluctuation. These more stable miRNAs most likely perform housekeeping duties, preserving vital cellular activities throughout the early stages of development.

Indicators of problems in embryonic development can also be found in patterns of miRNA expression during the preimplantation phase. For instance, embryos created via somatic cell nuclear transfer, which usually show impaired developmental competence, have been found to have higher levels of miR-145. Furthermore, lower blastocyst formation rates have been associated with higher expression of miR-24, highlighting the potential of certain miRNAs as indicators of embryonic quality and developmental potential [ 267 ]. Therefore, it may be possible to improve embryonic development and lower the frequency of embryo abnormalities by inhibiting the production of miRNAs that have negative effects. In this regard, it has been demonstrated that downregulating miR-145 increases the expression of genes linked to pluripotency, including POU5F1 and SOX2, which improves the rates at which blastocysts develop [ 267 ]. Conversely, effective development is supported by the expression of certain miRNAs within the embryo proper. For instance, it has been demonstrated that decreasing miR-130b expression during bovine preimplantation embryogenesis has a detrimental effect on developmental advancement, underscoring its beneficial function in early embryo growth and viability [ 234 ] Furthermore, decreased embryonic developmental competence has been linked to downregulation of miR-302, which is thought to contribute to maternal transcript clearance during embryogenesis, indicating its crucial role in promoting healthy early development [ 268 ] Fig. 2 . Fig. 2 Implantation and microRNAs involved. Illustration of the key stages of mammalian embryo implantation, highlighting the roles of specific microRNAs (miRNAs) at each step. This figure depicts how miRNAs regulate cellular communication, trophoblast invasion, and endometrial receptivity, emphasizing their critical influence on successful implantation and early pregnancy establishment

The role of embryonic MiRNAs in embryo implantation

The embryo attaches to and implants into the uterus after cell lineage definition and differentiation; this process is epigenetically controlled at both transcriptional and post-transcriptional levels. Successful implantation and subsequent development are ensured by the well-established bidirectional connection between the embryo and the maternal environment, which occurs in a time and space-coordinated manner. The oviduct and endometrial environment’s biochemical makeup and concentration of various elements, as well as the mother’s immune system, provide difficulties for the developing embryo. A delicately balanced maternal immune response that is suitably regulated throughout pregnancy to promote both maternal health and embryo survival is essential for successful embryonic development [ 269 ]. Thus, the synergistic interaction of endocrine, paracrine, and autocrine substances produced from the embryo and the mother leads to embryonic development and implantation. These include cytokines, growth factors and their receptors, chemokines, and adhesion molecules, including cadherins, selectins, and integrins. These all work together to promote successful implantation and early development [ 270 ].

It is commonly known that the blastomeres apically-basally polarize as the embryo approaches implantation, resulting in the segregation of two different cell populations at the blastocyst stage: the inner cell mass and the outer trophectoderm. The inner cell mass gives birth to the embryo proper, while the trophectoderm creates the outer layer that contributes to the placenta. Despite the paucity of available evidence, miRNAs are thought to be crucial for these crucial developmental processes, such as the segregation of embryonic cell lineages, embryonic outgrowth, and the implantation process that follows. During these critical phases of embryonic development, dysregulation of miRNAs can affect cell differentiation, which in turn might impede embryo implantation. This is corroborated by DICER knockout studies, which show that miRNAs play crucial regulatory roles in early development by preserving trophoblast stem cell populations by suppressing the cell cycle inhibitors Cdkn1a (p21) and Cdkn1c (p57) and maintaining epiblast pluripotency by preventing apoptosis [ 271 ]. Additionally, miRNA expression has been found in both first-trimester and term trophoblast cells in earlier research, with several miRNAs exhibiting differential expression between the two periods. This variance implies that throughout placental development, miRNAs have a role in regulating certain trophoblast cell traits and activities [ 272 ]. Likewise, the limited expression of miR-93 in the trophectoderm and future primitive endoderm and the increased expression of miR-106a in the inner cell mass imply that these miRNAs may be important regulators of embryonic cell differentiation and lineage specification [ 273 ]. The dynamic regulation of miRNAs during early embryonic development and implantation is further highlighted by the observation of differential expression of 526 miRNAs between embryonic outgrowths and blastocyst-stage embryos, including let-7b, miR-23a, miR-27a, miR-291a, miR-425, and miR-429 [ 274 ]. Likewise, differentiating the expression of certain miRNAs in trophoblast tissue and 8-cell stage embryos [ 275 ]. This further suggests that miRNAs produced from embryos can specifically control genes necessary for implantation by modulating their expression. However, implantation may also be adversely affected by the expression of certain miRNAs within the embryo. Studies have revealed that a number of miRNAs, such as let-7a, −7d, −7e, −7f, and − 7 g, express differently in dormant blastocysts than in their active counterparts. This suggests that these miRNAs may have an inhibitory effect on the activation and implantation of embryos [ 262 , 276 ].

The role of maternal MiRNAs in embryo implantation

Successful embryo implantation and the formation of pregnancy depend on the mother’s uterine receptivity in addition to the embryo’s implantation competence. In animals, uterine receptivity is modulated and embryo implantation is facilitated by temporal and spatial gene expression in uterine epithelial and stromal cells, which is controlled by variations in progesterone, prostaglandins, and embryonic signals like interferons. Effective pregnancy establishment, for instance, depends on the coordinated expression of adhesion molecules such as cadherins, selectins, and integrins as well as cytokines, growth hormones, and their corresponding receptors [ 277 – 281 ]. Integrins produced on the trophoblast cell surface and extracellular matrix proteins found in the endometrium interact to control cell adhesion and motility during embryo implantation, allowing for stable attachment and penetration of the embryo into the maternal tissue [ 282 – 284 ]. However, the endometrium secretes a variety of chemicals at this time, including miRNAs, in addition to integrins and adhesion molecules. Therefore, identifying non-coding molecular markers of endometrial origin that may be useful indicators of a successful pregnancy establishment should be made easier by clarifying the miRNA-mediated post-transcriptional regulatory processes involved in embryo implantation. For instance, distinct miRNA signatures are seen during the window of implantation (days 19–23), as well as in the early proliferative, late proliferative, early secretory, and late secretory phases, according to miRNA expression profiling of the endometrial epithelium in normally fertile women [ 24 – 28 ] During the menstrual cycle, stages have been identified in the endometrial epithelium of a healthy, fertile woman [ 285 ]. Furthermore, women who experience repeated implantation failure have been found to exhibit differential expression of endometrial miRNAs associated with cell adhesion and cell cycle pathways during the secretory phase. Furthermore, comparing the receptive and pre-receptive stages of the human endometrium has shown different miRNA expression patterns associated with cell cycle control, apoptosis, cell adhesion, and metabolism [ 286 , 287 ]. These results imply that, in response to its morphological and functional change from the perceptive to the receptive phase, the mammalian endometrial microenvironment dynamically adjusts the production of certain miRNAs, either boosting or decreasing them.

A crucial step in the creation of pregnancy is embryo implantation, during which the mother’s surroundings and the embryo both contribute certain chemicals that make the uterus receptive. Coordinated expression of a wide range of genes mediates this two-way “cross-talk” between the uterus and embryo. Localized stimulation or repression of certain endometrial gene networks at the embryo attachment sites is shown, for instance, by the differential expression of 518 and 374 genes between implantation and inter-implantation sites in the mouse and rat uterus, respectively [ 288 ].

The regulatory roles of several genes may be reflected in the insights obtained from individual miRNAs, since a single miRNA might target many genes. Therefore, a potent biological strategy to clarify the processes driving pregnancy establishment in mammals is to discover important miRNA signatures implicated in embryo-maternal cross-talk. In this regard, a prior study using Exiqon miRCURY LNA Arrays found that on gestation day 5, the uterus of a pregnant mouse showed a decrease in expression of miR-290-5p and miR-292-5p at implantation sites compared to inter-implantation sites, and an increase in expression of 13 miRNAs, including let-7a, let-7b, let-7c, and let-7d [ 289 ]. Similarly, at gestation day 5, another study using Exiqon miRCURY LNA Arrays found over 72 miRNAs that were differently expressed between implantation and inter-implantation regions in the mouse uterus. These miRNAs included miR-96, miR-30b, miR-290-3p, and miR-762 [ 290 ].

Likewise, it has been observed that several miRNAs in cattle, including miR-3902-3p, miR-1825, miR-885-3p, miR-504-3p, miR-92b, and miR-31b, vary between animals with high and low uterine receptivity [ 291 ]. At day 12 of gestation, the very prolific Chinese Erhu Alian breed and the Landrace × Large Yorkshire crossbreed showed distinct expression levels of endometrial miRNAs associated with angiogenesis, cell proliferation, and tissue remodeling in pigs [ 292 ]. These results imply that throughout mammalian development, miRNAs are essential for promoting embryonic survival and enabling embryo implantation. Additionally, functional investigations have demonstrated that endometrial miR-143, which is increased in the rat endometrium during the implantation phase in response to uterine decidualization and blastocyst activation, most likely aids in implantation by encouraging cell invasion and proliferation [ 293 ]. It’s interesting to note that endometrial-derived miRNAs may be transmitted to the embryo and affect the activation of embryonic genes in addition to modulating embryo implantation via controlling endometrial cell activities. In this regard, research conducted in vitro and in vivo by [ 285 ] Research has shown that the trophectoderm of the embryo absorbs endometrial miR-30d, which then triggers the expression of genes related to embryo adhesion. The crucial function of miR-30d in successful implantation was highlighted by a noteworthy study that found lower implantation rates when miR-30d knockout embryos were transplanted into miR-30d knockout recipients [ 294 ]. Furthermore, a number of endometrial miRNA gain and loss-of-function studies have demonstrated the critical functions of miR-200a, miR-429, and miR-145 in controlling embryo implantation and development ( Table 3 ) [ 295 – 297 ]. Table 3 A cross-species MicroRNA atlas delineates reproductive pathways from gametogenesis to successful implantation miRNA(s) Species Stage Sex Origin Experimental Evidence Function/Impact Reference(s) miR-99a, Human Oogenesis (EVs from follicular fluid) Female Contained inside little membrane-enclosed vesicles, released into the follicular fluid after ovulation. Crucial for the development of ovarian follicles and the maturation of meiosis. [ 298 ] miR-130b Human Oogenesis Female overexpressed in females whose eggs are not fertilized might affect the competence of oocytes [ 234 ] miR-132, miR-212, miR-214 Human Maturation of oocytes Female found in ovulation-related extracellular vesicles In connection with meiosis in cells [ 298 , 299 ] Let-7a Mouse Preimplantation Embryo grew to the 8-cell stage before declining into the blastocyst controls the transition from mother to zygotic [ 276 ] miR-130a, miR-21 Mouse Preimplantation Embryo increased to the 8-cell stage from the zygote stage aids in the development of the embryo [ 300 – 303 ] miR-205, miR-150, miR-122 Bovine Preimplantation Embryo Following the activation of the embryonic genome Participating in the specification of lineage [ 301 , 304 , 305 ] miR-218, miR-335, miR-449b Bovine Early vs. hatched blastocyst Embryo elevated in the blastocyst in the early stages Inherent in the early stages of development [ 306 – 308 ] miR-182 Mouse Preimplantation Embryo increased during the 4–8 cell stage and downregulated at the 2–4 cell stage Regulatory role unique to the development stage [ 309 ] miR-762 Mouse Implantation (uterine) Female expressed differently at the locations of implantation and inter-implantation (day 5) Adjust the receptivity of the uterus [ 310 , 311 ] miR-143 Rat Implantation (endometrium) Female Increase in the process of decidualization encourages the invasion and proliferation of endometrial cells [ 312 , 313 ] miR-30d Human/Mouse Implantation (endometrium embryo) Female Embryo Embryos absorb miRNA from the endometrium; knockdown hindered implantation encourages the expression of adhesion-related genes in embryos [ 285 , 294 , 314 ] miR-302 Human/Bovine Preimplantation Embryo Low competence is associated with downregulation. Controls the clearance of maternal transcripts. [ 309 , 315 ] miR-290-5p, miR-292-5p Mouse Implantation (uterine) Female Reduced at the location of implantation Potential modulators of the expression of uterine genes [ 316 ] miR-200a, miR-429 Mouse Implantation Female Studies of functional gain and loss improves decidualization and implantation [ 296 ] let-7a, let-7d, let-7e, let-7f, let-7 g Mouse Blastocyst dormancy Embryo Differences between activated and dormant blastocysts Associated with developmental arrest [ 276 ] miR-106a, miR-93 Mouse Embryo differentiation Embryo Expression differences between the inner cell mass and trophectoderm might regulate the division of lineages [ 317 , 318 ] miR-24 Human/Mouse Preimplantation Embryo Elevated levels linked to limited yield of blastocysts adverse impact on development [ 319 , 320 ]

Dysregulated MiRNAs in male and female infertility

Male infertility and MiRNA dysregulation

Research on the function of miR-34b/c in spermatogenesis yields conflicting findings. According to some in vitro studies, the initial cleavage division requires both miR-34b/c and miR-449a/b/c [ 73 , 321 ]. According to other research, mice lacking miR-34b/c and miR-449 continued to produce sperm normally [ 322 ]. Notably, these microRNAs were identified as paternal microRNAs because they were only present in sperm cells and not in oocytes, despite having the same “seed sequence” and being in the same family [ 73 , 322 ]. Although miR-34b/c and miR-449 are not necessary for male fertility, the previous work found that their combined absence impairs spermatogenesis and male infertility due to chromatin condensation problems and sperm formation disturbances [ 322 ]. By targeting the activating transcription factor 1 (ATF1) gene, which is expressed in spermatocytes, miR-34c has also been demonstrated to induce germ cell death [ 71 ]. Spermatocytes and round spermatids were found to have elevated levels of miR-34c, and it was demonstrated that inhibiting miR-34c decreased germ cell death [ 200 ].

The chromosomal location of the human miR-21 gene has been determined to be chromosome 17q23.2. The gene has been found and described [ 160 , 323 ]. Maintaining the SSC population requires MiR-21. Temporarily inhibiting miR-21 in SSC-enriched cultures led to increased death of germ cells and a significant reduction in the development of spermatogenesis colonies after transplantation into recipient mice. Moreover, miR-21 expression is regulated by the transcription factor ETV5, which is essential for SSC self-renewal [ 324 , 325 ]. Therefore, a crucial regulatory mechanism for SSC maintenance is the ETV5/miR-21 axis [ 63 ].

One of the most studied microRNAs associated with male infertility is miR-34. 40 of the 106 semen samples examined in a recent research were classified as normozoospermic, 47 as asthenozoospermic, and 19 as oligozoospermic [ 321 , 326 ]. According to the results, semen samples from oligozoospermic patients had significantly lower levels of miR-34b-5p, miR-34c-3p, and miR-34b-3p than those from normozoospermic patients [ 326 ]. Furthermore, a number of studies have connected decreased levels of miR-34b and miR-34c to spermatogenesis disturbances, impaired meiosis, non-obstructive azoospermia, decreased male fertility, and faulty sperm maturation [ 322 , 327 – 331 ]. Consistent with these findings, male infertility has also been linked to aberrant regulation of miR-449, mostly because of decreased sperm motility [ 327 ].

Wang C. and colleagues examined seminal plasma samples from infertile and fertile males of the same age group in comprehensive research with 457 patients. Seven microRNAs were found to be considerably elevated in patients with asthenozoospermia and downregulated in those with azoospermia [ 332 ]. The previously reported miR-34c-5p was one of the microRNAs found, along with miR-122, miR-146b-5p, miR-181a, miR-374b, miR-509-5p, and miR-513a-5p [ 332 ]. The seminal plasma of people with non-obstructive azoospermia had considerably higher levels of miR-19b and let-7a than those from fertile control participants, according to a different research that included 192 patients with idiopathic male infertility [ 333 ]. Each of these microRNAs may contribute to the development of new targeted treatments as well as serve as diagnostic biomarkers for idiopathic male infertility.

Men with asthenospermia had lower levels of miR-10b and miR-135b, whereas men with oligoasthenospermia had significantly lower levels of miR-34c-5p, miR-181a, and miR-122 [ 334 , 335 ]. Several additional research have also identified a range of microRNAs that might be useful indicators for male infertility diagnosis [ 330 , 336 – 338 ]. MicroRNAs are attractive prospects as supplemental diagnostic tools due to their great sensitivity and possibility for early detection, even if they are unlikely to completely replace proteins as biomarkers. According to a recent research, MRX34, a synthetic microRNA mimic that is administered in a lipid capsule and is intended to imitate miR-34a, effectively reduced tumor development [ 339 ]. Anti-miRs, on the other hand, impede the action of certain microRNAs by binding to them. Both anti-miR medicines and microRNA mimics have been tried for a variety of viral infections and malignancies, but they have not yet been investigated as therapy for male infertility [ 340 , 341 ]. Important microRNAs that control spermatogenesis, germ cell apoptosis, and stem cell maintenance, such as miR-34b/c, miR-449, and miR-21, are important in male infertility. Their potential as diagnostic indicators and new therapy targets is highlighted by their frequent aberrant expression in conditions such as azoospermia and oligozoospermia.

Female infertility and MiRNA dysregulation

Finding miRNAs with changed expression in endometriosis has been the subject of several investigations; more recently, non-invasive materials such as saliva have been employed in these studies [ 342 , 343 ]. One of the most often used sample types in endometriosis research is blood, which is obtained by a minimally invasive method. Papari et al. (2020), for instance, used blood plasma in their investigations [ 344 ]. MiR-199a-3p, miR-143-3p, miR-340-5p, let-7b-5p, miR-21-5p, miR-103a-3p, miR-17-5p, and miR-20a-5p were all found to be at lower levels. In the study by Jia et al. (2013), it was noteworthy that miR-22 was also shown to be downregulated in women with endometriosis, along with miR-17-5p and miR-20a-5p [ 345 ]. However, while Bashti et al. (2018) considered disease stage in their analysis, neither research showed differences associated with endometriosis severity stages [ 346 ]. The most recent study found that among the miRNAs that were differently expressed in endometriosis-affected women, miR-145 exhibited elevated expression while miR-31 was significantly downregulated. Furthermore, miR-122 and miR-199a were also detected in blood serum samples [ 347 ]. Women with endometriosis had higher levels of miR-125b-5p, miR-150-5p, miR-342-3p, miR-451a, and miR-30c-5p in their blood serum samples [ 348 , 349 ]. On the contrary, miR-135a, miR-3613-5p, and let-7b revealed decreased amounts [ 348 , 350 ].

The majority of adenomyosis research has been conducted on endometrial tissue samples, as opposed to endometriosis, where differentially expressed miRNA profiles have been extensively studied in biofluids. These studies have shown that the eutopic and/or ectopic endometrium of women with adenomyosis has overexpressed miR-17, miR-191, miR-181b, and miR-145 [ 351 – 353 ]. MiR-10b, miR-200c, let-7a, miR-30c-5p, and miR-183 stood out among the miRNAs that were markedly downregulated [ 352 – 356 ]. However, miRNA expression levels can be altered by treatments such as high-intensity focused ultrasound; for instance, miR-191-5p levels were shown to drop after such therapy [ 357 ]. Additional research, including Juarez-Barber et al. (2023) [ 358 ], Some research have focused on extracellular vesicles generated by endometrial organoids obtained from women with adenomyosis, which can be maintained in vitro, rather than examining miRNAs in total endometrial tissue.

GCs and CCs, which encircle the oocyte in ovarian follicles, have been the primary focus of studies examining miRNAs in patients with decreased ovarian reserve (DOR). This emphasis is based on the hypothesis that aberrant control by these supporting cells in the antral follicle environment may lead to decreased oocyte quality in DOR. Notably, it was discovered that individuals with DOR had lower levels of miR-106a, which targets ASK1, and miR-221-3p, which targets the FOXO1 gene [ 359 , 360 ]. Variations in these miRNAs were associated with higher granulosa or cumulus cell apoptosis in both investigations. Furthermore, Woo et al.‘s study revealed decreased levels of miR-16-5p, which led to an activation of the MAPK and WNT3 pathways, improving cell division, proliferation, and apoptosis [ 361 ]. The DOR profile may be similar to that of aged ovaries, since the same study also discovered increased levels of miR-128-3p, which resulted in decreased expression of TGFBR1 and a change previously observed in older women. Furthermore, lower levels of SMAD4 and YAP1 were associated with higher expression of miR-6881-3p and miR-484 in women with DOR, respectively, which led to greater granulosa cell death [ 133 , 143 ]. Studies on miRNA profiles have expanded to include follicular fluid (FF) in addition to cells directly engaged in folliculogenesis. The amounts of different miRNAs within FF exosomes have been thoroughly investigated since exosomes are essential for cell-to-cell communication. The most prevalent miRNAs in FF exosomes from women with reduced ovarian reserve were found to be miR-342-3p, miR-483-3p, and miR-625-3p, whereas Shen et al. recently revealed lower expression of miR-122-5p, miR-1246, and miR-130b-3p [ 362 ]. The average age of the DOR and control groups with normal ovarian reserve did not differ statistically significantly, which is one of the study’s strengths. In contrast, the age difference between the groups was statistically significant in the study by Xie et al., even though downregulated miR-21-5p and elevated miR-28-3p, miR-155-5p, and miR-29a-5p were found [ 362 ].

Small interfering RNAs (siRNAs) and infertility

According to recent studies, male infertility and impaired spermatogenesis are associated with small RNA dysregulation, particularly in NOA instances [ 309 , 363 , 364 ]. Reproductive biology is seeing a sharp increase in the study of short RNA (sRNA) activities, with distinct roles being played by various sRNA subtypes. For example, it is known that miRNAs regulate molecular pathways that are essential for spermatogenesis, apoptosis, and germ cell development [ 365 , 366 ]. Moreover, research has looked at changes in miRNA expression in males who are infertile or subfertile in comparison to healthy controls, finding several miRNAs that exhibit differential expression [ 365 , 367 ]. Likewise, transposon silencing and preserving germ cell genomic integrity depend on piRNAs [ 368 ]. Consequently, male infertility may arise from interruption of the piRNA pathway [ 368 , 369 ]. Moreover, because of their stability, specificity, and ability to detect both healthy and diseased situations, short RNAs in particular, microRNAs, or miRNAs, have drawn interest as possible biomarkers [ 370 ], making them perfect for use in clinical settings and reproductive biology.

The specific roles of short RNAs in male reproduction and fertility remain unclear despite their promise. In particular, it is yet unknown which small RNA expression patterns are associated with successful testicular sperm extraction (TESE) and whether they have an effect on the course of pregnancy. A critical gap in the treatment of azoospermic patients might be filled by developing a better knowledge of small RNAs in these domains, which could improve the prediction of TESE outcomes, find suitable short RNAs as biomarkers, and provide insight into variables influencing pregnancy success.

It has been shown that miRNA is not necessary for oocyte maturation [ 204 ], and female Zp3-Cre; Dgcr8lox/lox or Zp3; Droshalox/lox eggs lacking miRNA are viable [ 371 – 373 ]. Given that oocytes defective in Dgcr8 or Drosha (Dgcr8 cKO or Drosha cKO) remain fully normal and fertile, but oocytes missing Dicer (Dicer cKO) display spindle defects and sterility, endo-siRNAs appear to be essential for oocyte maturation [ 371 , 372 , 374 ]. They injected sperm from Dicer and Drosha cKO males into Drosha cKO eggs and evaluated their developmental potential to see if the lack of maternal and paternal miRNAs and/or endo-siRNAs results in combined detrimental effects on fertilization and early embryonic development.

Gamete function and the early stages of embryonic development are greatly impacted when endo-siRNAs are disrupted. By controlling transcripts involved in spindle assembly and chromosomal segregation, siRNAs in oocytes are essential for controlling gene expression during meiosis. Spindle abnormalities, decreased meiotic development, and infertility result from aberrant transcript accumulation caused by the absence of Dicer, the enzyme that produces siRNA. These findings demonstrate how crucial endo-siRNAs are to maintaining the molecular stability of developing oocytes.

Though less research has been done on siRNAs in sperm than in oocytes, there is mounting evidence that they are important for maintaining genomic integrity, managing transposable elements, and maybe guiding epigenetic reprogramming during spermatogenesis. Male germ cells that lack Dicer exhibit aberrant sperm shape, reduced motility, and a reduced capacity for fertilization. These results show that the creation of functional, high-quality sperm depends on proper siRNA synthesis and activity.

The combined effect is evident when both sperm and oocytes lack functioning siRNA pathways, as occurs when Dicer or Drosha-deficient sperm are injected into Drosha-deficient oocytes. The embryos usually stop developing in the early stages, yet fertilization continues. This suggests that siRNAs from the maternal and paternal genomes play a critical role in post-transcriptional regulation, which maintains the stability of early zygotic transcripts and ensures that cell division proceeds correctly.

All of these findings point to the crucial role endo-siRNAs play in gamete maturation and the early phases of embryonic development. Their critical significance as crucial regulators of reproductive outcomes is highlighted by the fact that disruption of their normal activity can affect gamete quality, reduce fertility rates, and impede embryo growth.

Long noncoding RNAs (lncRNAs) in infertility

Epigenetic regulation and chromatin remodeling by LncRNAs

Because of their function in controlling transcription and chromatin remodeling, long non-coding RNAs, or lncRNAs, have attracted a lot of attention. Over 200 nucleotides long, these transcripts fold into intricate structures that interact with proteins, RNA, or DNA to affect cellular signaling pathways and gene expression [ 375 , 376 ]. Indeed, although lncRNAs are typically expressed at lower levels than mRNAs, they are essential for regulating the patterns of gene expression throughout cell differentiation and development. Furthermore, they play a significant role in both normal physiology and disease situations due to their highly specialized expression, which is shown in both certain cell types and specific cancer types [ 377 ]. In epithelial ovarian cancer, overexpression of SNHG10 has been demonstrated to markedly suppress tumor growth and the epithelial-mesenchymal transition. In ovarian cancer, the SNHG10/miR-200a-3p/BIN1 regulatory pathway has been found to be a target for therapeutic intervention and a possible biomarker for prognosis [ 377 ]. Numerous tumor forms have been shown to exhibit dysregulation of the long non-coding RNA HOTAIR. Its overexpression is associated with poor clinical outcomes and increased metastatic potential in epithelial ovarian cancer (EOC), most likely due to changes in the expression of metalloproteinase and genes implicated in the epithelial-mesenchymal transition [ 378 ].

One well-known transcriptional control method is DNA methylation. An important link between lncRNAs and oncogenic processes is being shown by mounting evidence of their direct interaction with elements of the epigenetic apparatus, such as DNA methyltransferases and chromatin-modifying enzymes. Knowing how lncRNAs, epigenetic changes, and transcriptional control interact dynamically provides important information on how genes are regulated and identifies trustworthy biomarkers associated with treatment resistance. Notably, one of the few methods that can endogenously reactivate tumor suppressor genes in a locus-specific manner is targeting lncRNAs [ 379 ]. Only a small portion of the large repertoire of lncRNAs encoded in the human genome has been fully described, annotated, and functionally studied, despite the promising discoveries. Clarifying the precise functions of cancer-associated lncRNAs and how they contribute to treatment resistance in ovarian cancer is still crucial. Furthermore, more research is necessary to fully understand the molecular relationship between lncRNA expression and epigenetic control.

LncRNAs in endometriosis, PCOS, and testicular dysfunction

Endometriosis

The competitive endogenous RNA (ceRNA) mechanism is a complex, multilevel regulatory network in which lncRNAs might participate by acting as molecular sponges for miRNAs. The complex interactions between messenger RNAs (mRNAs), circRNAs, miRNAs, and lncRNAs are depicted in this model, underscoring their coordinated functions in post-transcriptional gene regulation [ 380 ]. First, samples from four patients with ovarian endometriosis were subjected to thorough lncRNA expression profiling utilizing a Human lncRNA Expression Microarray. Analysis of ectopic endometrial lesions showed a considerable dysregulation of 4,088 mRNAs and 948 lncRNAs compared to eutopic endometrial tissues [ 381 ]. Furthermore, Liu et al.‘s high-throughput sequencing investigation showed that women with endometriosis had substantially different expression levels of 1,200 lncRNAs in the eutopic endometrium and 695 lncRNAs in the ectopic endometrium when compared to healthy controls [ 382 ]. In the pathophysiology of EMS, aberrant expression of lncRNAs plays several functions, especially in immunologic situations that will be covered in depth.

PCOS

lncRNAs are important modulators of cellular functions as cancer, apoptosis, differentiation, and proliferation. They use a variety of methods to carry out their tasks, including interactions with RNA-binding proteins, chromatin-modifying complexes, and ceRNA networks [ 383 – 385 ]. According to earlier studies, lncRNAs could be involved in follicular development. For example, one study found that Neat1 KO mice had lower blood progesterone levels and decreased corpus luteum function, which prevented them from becoming pregnant. The role of lncRNAs in women with and without PCOS has been investigated in ten studies to far [ 386 – 395 ].

Three investigations have looked at lncRNAs in PCOS-afflicted women’s peripheral blood leukocytes [ 386 , 387 , 395 ]. Liu et al. evaluated peripheral blood leukocytes from women with PCOS ( n = 23) and healthy control patients ( n = 17) to determine the expression of C-Terminal Binding Protein 1 antisense RNA (CTBP1-AS) [ 386 ]. Researchers found that women with PCOS had considerably higher levels of CTBP1-AS expression. Furthermore, Liu et al. found that PCOS patients had significantly higher levels of the lncRNA SRA than did healthy controls [ 387 ]. According to Li et al., women with PCOS had significantly higher levels of lncRNA H19 expression in peripheral blood leukocytes than did healthy controls. Additionally, those with greater levels of lncRNA H19 showed a much higher chance of getting PCOS, indicating that it may be a biomarker for early diagnosis in vulnerable groups. Due to constraints including small sample sizes and the use of peripheral blood leukocytes, these results should be evaluated cautiously as they might not accurately reflect the systemic character of PCOS as an endocrine illness.

LncRNAs in the GCs and cumulus cells of PCOS-afflicted women have been the subject of four investigations [ 388 – 390 , 394 ]. In two studies, lncRNA expression patterns in GCs or cumulus cells from women with and without PCOS were compared using microarray analysis. In the cumulus cells of PCOS patients, Huang et al. found that 620 lncRNAs were substantially elevated, whereas just three lncRNAs were downregulated. As for Liu et al. [ 390 ]. Further illustrating the extensive changes in lncRNA expression linked to PCOS, Liu et al. discovered that 692 lncRNAs were elevated and 170 lncRNAs were downregulated in granulosa cells from women with the disorder [ 389 ]. All of these findings suggest that lncRNA up-regulation was more prevalent in PCOS than down-regulation.

All things considered, these investigations have found a number of lncRNAs that seem to play a role in PCOS development. Nevertheless, discrepancies in their results suggest that there is still not enough data available to make firm judgments at this time.

Testicular dysfunction

Transcripts longer than 200 nucleotides that do not encode proteins are commonly referred to as long non-coding RNAs, or lncRNAs. Their capacity to engage with molecular partners via base pairing or certain secondary structures underlies their functional responsibilities. When lncRNAs bind, they may act as allosteric regulators, scaffolds, guides, or molecular sponges (baits) that aid in the formation of ribonucleoprotein complexes [ 17 , 396 ]. Numerous biological processes require lncRNAs, which are often discovered to be aberrantly produced in malignancies where they can act as oncogenes or tumor suppressors [ 397 ]. Lately, evidence of lncRNAs’ potential involvement in TGCT has begun to surface [ 398 ].

The XIST transcript, which is expressed in testicular germ cell tumors (TGCTs) after the acquisition of extra X chromosomes, was the first to be linked to lncRNAs and TGCTs [ 399 ]. With the ability to differentiate seminomas from non-seminomatous tumors, XIST expression and the demethylation state of its promoter have recently been proposed as tissue-specific biomarkers for TGCTs [ 400 ].

The transcript of Testis Developmental-Related Gene 1 (TDRG1) is one of the most well-researched lncRNAs associated with TGCTs. Seminomas have a substantial upregulation of TDRG1, which promotes tumor development, progression, and resistance to cisplatin treatment [ 401 – 404 ].

There is a correlation between the expression of lncRNA TDRG1 and another lncRNA, H19, in TGCTs. In men, H19 is usually expressed only from the maternal allele and is encoded via a paternally imprinted gene. H19 is often elevated in TGCTs, most likely due to loss of imprinting, which might be a reflection of carcinogenesis during the early stages of embryonic development, when biallelic expression of H19 is typically seen [ 405 – 409 ].

It has been suggested that H19 acts as a molecular sponge for miRNA-106b-5p, which typically inhibits TDRG1, hence increasing TDRG1 expression in the cisplatin-resistant TCam-2 cell line. By reducing the inhibitory impact of miRNA-106b-5p, this sequester increases cell survival after cisplatin treatment [ 410 ].

Several carcinogenic signaling pathways in melanoma are favorably regulated by the lncRNA SPRY4-IT1, which functions as a miRNA sponge [ 411 ]. According to a recent study, human TGCTs have high levels of SPRY4-IT1 expression. Transient knockdown of SPRY4-IT1 in two TGCT cell lines resulted in decreased invasion, migration, and proliferation of cells as well as a notable reduction in Akt phosphorylation [ 412 ].

In the testes of infertile men with mixed maturation arrest, NLC1-C, also known as long intergenic non-protein-coding RNA162 (LINC00162), was shown to be downregulated in the cytoplasm but accumulated in the nucleus of spermatogonia and primary spermatocytes in contrast to normal controls. By interacting with nucleolin, the nuclear accumulation of NLC1-C boosted the proliferation of a testicular embryonal carcinoma cell line. This, in turn, suppressed the transcription of two miRNAs known for their tumor-suppressive properties, miR-320a and miR-383, which in turn negatively regulate the expression of NLC1-C [ 78 ].

The 5′ portion of the HOXA gene cluster is the source of the 3,764-nucleotide-long non-coding RNA (lncRNA) known as HOXA transcript at the distal tip (HOTTIP). It has become a promising diagnostic and therapeutic target for a wide range of human tumors and is well known to be an oncogenic lncRNA [ 413 ]. In the testicular embryonal cancer cell line NT2, HOTTIP was discovered to be extensively expressed. Overexpression of HOTTIP increased cell proliferation, whereas its knockdown decreased it. The findings also suggested that HOTTIP upregulates the oncogenic transcription factor HOXA13 by acting as a molecular sponge for the anti-proliferative microRNA miR-128-3p [ 414 ].

PIWI-Interacting RNAs (piRNAs) in infertility

Mechanism: role in transposon Silencing and germline genome integrity

Modification of PiRNAs and Piwi proteins

Similar to siRNAs, the majority of mature piRNAs have 2′-O-methylated 3′ ends, while the 5′ end has a phosphate group [ 32 , 155 , 165 , 415 – 418 ]. The Drosophila homologue of Arabidopsis HEN1, DmPimet (piRNA methyltransferase)/DmHEN1, is responsible for the 2′-O-methylation [ 417 , 418 ]. Since 2′-O-methylation is eliminated in Dmhen1 mutants, average piRNA length and abundance are decreased, suggesting that this modification aids in shielding mature piRNAs from deterioration. These mutants are nonetheless alive and fertile while showing a slight reduction in transposon silencing. Despite the possibility that the existing Dmhen1 alleles may not constitute total loss-of-function mutations, our findings suggest that 3′-end modification is not necessarily necessary for piRNA function.

The methyltransferase PRMT5, which catalyzes the production of symmetrical dimethyl arginines (sDMAs), has recently been found to have substrates in the Piwi proteins Aub and Ago3. For proteins with Tudor domains, these sDMA alterations act as recognition sites [ 419 ]. Tudor (Tud), the family’s founder member and one of the 23 Tudor domain-containing proteins discovered in Drosophila, is crucial for the correct localization of Aub in the germline and for the assembly of germplasm [ 420 , 421 ]. Furthermore, it has been demonstrated that the Tudor domain proteins Krimper, Spindle-E, and Tejas are essential for the localization of PIWI proteins, piRNA synthesis, and transposon silencing [ 422 – 425 ]. These results imply that the development of higher-order protein complexes that promote piRNA synthesis and transposon silencing is facilitated by the dimethylation of Piwi family members.

Transposons and other repeating elements are the source of the majority of Drosophila piRNAs, and mutations that impact piRNAs cause widespread transposon overexpression. Thus, it is thought that transposon activity is directly regulated by piRNA–PIWI complexes. Transposon silencing is mostly achieved via post-transcriptional degradation of their RNA, as evidenced by in vitro experiments showing that piRNAs linked to PIWI proteins cause homology-dependent cleavage of target transcripts [ 426 – 428 ]. Notably, the Nuage, a perinuclear organelle that is conserved across species and is essential for RNA metabolism in germ cells, contains a concentration of many piRNA pathway proteins, including Aub and Ago3 [ 426 – 431 ]. Furthermore, transposon insertions into the introns of protein-coding genes prevent them from being silenced by the piRNA pathway. This suggests that only after nuclear export can piRNAs linked to Aub and Ago3 target and cleave mature transposon transcripts in a homology-dependent manner. In this concept, the splicing process removes the piRNA-targeted regions, preventing repression in protein-coding genes containing intronic transposon sequences.

However, a number of lines of evidence indicate that piRNAs operate at different regulatory levels. Notably, Piwi, the original member of the PIWI family, interacts with HP1a, localizes to the nucleus, and contributes to the development of heterochromatin in somatic cells [ 432 , 433 ]. Moreover, reduced HP1a association with the telomere-specific transposon TART results from mutations in spn-E, which encodes a putative helicase necessary for piRNA production [ 434 ]. These results suggest that piRNAs attached to Piwi proteins control the establishment of heterochromatin, which in turn suppresses transcription. This idea is supported by the fact that decreased DNA methylation in mouse testes is a result of mutations in piRNA pathways. Nevertheless, the mouse Piwi protein Mili interacts with translation initiation proteins, and piRNAs have also been found in polysome fractions, indicating a possible function in improving translation [ 435 , 436 ]. These results suggest that piRNAs may potentially regulate translation.

Germline genome

The lengthier counterparts of the commonly expressed siRNAs and miRNAs are piRNAs, which typically have a length of 23–31 nucleotides. Understanding their biological significance has been largely dependent on their sequences and the conserved function of PIWI proteins in inhibiting transposable elements throughout the mammalian germline.

Either transcripts of active transposable element (TE) copies or RNA generated by specific genomic areas called piRNA clusters are the sources of piRNAs. These clusters are a key part of the cellular defense mechanism against TE mobilization and include damaged TE fragments [ 431 , 437 , 438 ]. The majority of piRNAs generated from piRNA clusters include antisense sequences corresponding to transposable element TE mRNAs, which allows them to use base pairing to direct PIWI proteins to their TE targets. PIWI-mediated identification of TE transcripts causes cleavage in the cytoplasm, which results in TE RNA destruction and piRNA amplification at the same time. The cleavage fragments are then further processed to create additional piRNAs. By retaining TE sequences within piRNA clusters, this feedback mechanism enables the piRNA pathway to operate similarly to an adaptive immune system by preserving a molecular memory of previous transposon incursions. The piRNA pathway allows for a quick and targeted reaction to acute transposable element activation by amplifying piRNAs complementary to active transposon sequences. PIWI proteins function at the chromatin level, directing the deposition of restrictive histone modifications and DNA methylation to suppress TE transcription in addition to facilitating targeted cleavage of TE mRNAs in the cytoplasm [ 439 , 440 ]. Therefore, the piRNA pathway limits germline transposable element activity on two levels.

For TEs to be silenced in mice, DNA methylation is essential. This silencing occurs within a constrained developmental window during the embryonic development of male germ cells, after a phase of universal genome demethylation. This time frame is crucial for the destiny of spermatogenic cells because if retrotransposon sequences scattered throughout the genome are not remethylated, they become activated, leading to meiotic abnormalities and eventually sterility [ 441 ]. The function of piRNAs in directing DNA methylation to certain genomic loci is supported by several lines of evidence. Notably, it has been noted that a number of piRNA pathway proteins localize into the nucleus, including MIWI2, TDRD9, and MAEL [ 438 , 442 – 444 ]. While MIWI2 expression is restricted to a small developmental window that precisely corresponds with the time of de novo DNA methylation in embryonic spermatocytes, TDRD9 and MAEL are expressed constantly throughout the development of male germ cells. Additionally, piRNAs have been linked by genetic research to the regulation of the development of de novo DNA methylation patterns at transposable element regulatory areas in the mouse male germline [ 167 , 438 , 445 ]. DNMT3L is essential for creating new DNA methylation marks and is a crucial cofactor for the de novo DNA methyltransferases DNMT3A and DNMT3B. The DNMT3L knockout mice’s phenotypic abnormalities are quite similar to those of animals lacking important elements of the piRNA pathway, such as the PIWI proteins MILI and MIWI2, and they all show meiotic arrest during spermatogenesis and germ cell death. Furthermore, methylation patterns on retrotransposon sequences cannot be restored in mice deficient in MILI or MIWI2 [ 445 ]. In contrast, DNMT3L mutants continue to generate piRNAs [ 438 ]. These results show that the methylation of TEs is directed by the piRNA pathway, which functions upstream of the DNA methylation machinery. The piRNA pathway plays a crucial role in TE repression in the germline by coordinating both post-transcriptional cleavage and epigenetic silencing via DNA methylation. In male germ cells, PIWI proteins, particularly MIWI2, play a crucial role in initiating de novo methylation during a crucial developmental window. When this route is disrupted, meiotic stoppage, TE derepression, and ensuing sterility occur.

PiRNA defects in azoospermia and poor embryonic development

To investigate the function of the PARN family ribonucleases in piRNA trimming, mouse models with Pnldc1 or Parn deficient were created [ 446 – 452 ]. Although Parn mutant mice are fatal to the embryo, there is no clear connection to piRNA biogenesis [ 452 ]. On the other hand, in mice, Pnldc1 is genetically necessary for piRNA trimming. Male Pnldc1 knockout mice are infertile, although the mice are nonetheless alive. Reduced amounts of mature piRNAs are seen in germ cells deficient in PNLDC1, coupled with an accumulation of untrimmed pre-piRNA intermediates that retain 3’ extensions that are typically eliminated during trimming [ 447 – 449 ]. Moreover, MIWI is significantly more impacted than MILI by PNLDC1 deficiency, as seen by dramatic decreases in MIWI protein levels and MIWI-associated piRNAs [ 447 ]. Unprocessed pre-piRNA accumulation disrupts downstream piRNA functions, resulting in partial transposon silencing and ensuing abnormalities in germ cell development [ 447 – 449 ]. Because its absence results in intermittent meiotic abnormalities during spermatogenesis and stops development at the elongated spermatid stage, which leads to adult azoospermia, PNLDC1 is therefore necessary for male fertility in mice [ 453 ]. The phenotypic effects of Pnldc1 knockouts are notably less severe than those of Tdrkh knockouts, with milder impairments in piRNA synthesis and germ cell development, even though both Pnldc1 and Tdrkh knockout animals have similar deficits in piRNA 3’-end trimming [ 454 , 455 ]. This implies that TDRKH has roles other than facilitating piRNA trimming, which is consistent with its suggested function of directly attracting MIWI to enable its integration into the piRNA pathway [ 447 – 449 , 454 , 455 ]. It is yet unclear how PNLDC1 affects other elements of the piRNA processing pathway, despite being the 3′–5′ exonuclease in charge of piRNA trimming. Given the strong dependency of these processes, it is necessary to investigate how improper trimming affects the protective modification, such as the 2′-O-methylation of piRNAs mediated by HENMT1, which is a crucial step in piRNA maturation [ 456 , 457 ]. Additionally, compared to Pnldc1 single knockouts, Pnldc1::Henmt1 double knockout animals have more severe symptoms, such as smaller testicles and noticeable spermatogenic abnormalities [ 453 , 458 ]. Questions concerning possible further functions of PNLDC1 or the trimming complex beyond pre-piRNA 3′-end processing are raised by the discovery that PNLDC1 is the essential trimmer in the piRNA processing pathway. According to recent data, PNLDC1 may potentially affect mature piRNAs’ preference for length, suggesting potential interactions with upstream elements that aid in defining accurate trimming termination signals [ 459 ]. All things considered, PNLDC1 has been shown to be the primary piRNA trimmer in the mouse germline and to be crucial for spermatogenesis. This emphasizes how crucial it is for male fertility and makes it an intriguing area for further research.

The piRNA pathway is essential for preserving the integrity of the germline genome and controlling the expression of genes required for spermatogenesis and male fertility. Findings from research on humans and mice highlight the critical role of piRNA trimming, which is carefully regulated by PNLDC1 and its cofactor TDRKH. A major genetic underpinning for idiopathic male infertility is revealed when loss-of-function mutations disrupt this trimming phase, impairing piRNA maturation and resulting in faulty spermatogenesis and non-obstructive azoospermia. Nevertheless, little is known about the piRNA trimming complex’s precise molecular makeup, dynamic assembly, and interactions with upstream piRNA biogenesis and downstream protective modifications such as 2’-O-methylation. To completely comprehend the function of piRNA processing in germline development and to find viable treatment options for male infertility, these pathways must be further clarified.

The biggest family of short non-coding RNAs produced by animal cells is piRNA [ 34 , 460 , 461 ]. Retrotransposons and other mobile genetic elements in germline cells are silenced by piRNA–PIWI complexes, which are formed when piRNAs bind to PIWI proteins. By using sequence complementarity to identify target transcripts, these complexes mediate their cleavage, limiting transposon mobilization and maintaining the genomic integrity necessary for fertility [ 34 ]. Transposon expression may be silenced as a result of piRNA action in gene regulation [ 426 ], because transposon sequences are antisense to the majority of piRNA sequences [ 462 ]. It is thought that piRNAs’ transposon-silencing function is a crucial stage of embryonic development, especially in the germline. The genome experiences profound epigenetic remodeling at this period, which includes worldwide DNA demethylation that may reactivate transposable elements. In order to preserve genomic stability, piRNAs are essential in suppressing these elements through their interaction with PIWI proteins. Transposon activation can impair gene activity and germ cell integrity in the absence of efficient piRNA-mediated silencing, which can eventually result in developmental arrest, infertility, or embryonic death [ 438 ]. Because piwi proteins directly bind with piRNAs, they are essential for enabling transposon silencing in human testes and invertebrate germ cells. These piwi proteins are members of the Argonaute family, which is essential to miRNA-mediated gene silencing pathways. In mammals, MIWI, MIWI2, and MILI are important members. These piwi proteins are guided by the precise sequences of piRNAs to identify and efficiently silence their transposon targets [ 438 ]. Potential infertility results from a correlation between increased transposon expression and decreased expression of these PIWI proteins [ 438 , 463 , 464 ]. Prior research has shown that elevated miR-17 expression inhibits tissue development [ 465 ]. Subsequent investigation showed that the infertility rate was much greater in miR-17 transgenic mice. The purpose of this study was to look into the precise function of miR-17 throughout the development of the embryo.

These piRNAs were divided into six groups according to how closely their sequences resembled those of miR-17-5p: Six nucleotides in Group I’s 5′ end matched the miR-17-5p seed region; six nucleotides in Group II were complementary (antisense) to the seed region; over six nucleotides in Group III were homologous to miR-17-5p; five nucleotides in Group IV were homologous to miR-17-5p; six nucleotides were found in Group V’s middle of the piRNAs; and six nucleotides were found at the 3′ end of the piRNAs. When comparing the oocytes of miR-17 transgenic mice to wild-type controls, they found that eight Group I piRNAs were markedly downregulated. Likewise, the transgenic mice in Group II exhibited decreased expression of piRNAs. A more thorough examination of these two groups showed a significant drop in the quantity of oocytes, sperm, and embryos at different stages of development. In contrast, Groups IV, V, and VI had negligible or no discernible changes in comparison to controls, whereas Group III piRNAs displayed fold changes similar to Group I.

Because the inability to silence TEs results in genomic instability in germ cells, deficiencies in the piRNA pathway are linked to defective embryonic development. By interfering with DNA methylation and chromatin control, disruptions in piRNA synthesis or PIWI protein activity result in aberrant gametes and prevent appropriate zygotic genome activation. Consequently, early developmental halt or degeneration is common in embryos derived from piRNA-deficient gametes.

Circular RNAs (circRNAs) in infertility

In contrast to linear RNAs, circular RNA (circRNA) is a unique kind of RNA distinguished by a covalently closed loop structure. Previously thought to be non-coding, circRNAs have lately garnered increased scientific attention as a result of improvements in detection and characterisation brought about by advancements in sequencing technology [ 466 – 468 ]. Many studies regard circRNAs to be numerous and varied endogenous RNAs that play distinct regulatory activities. CircRNAs are classified into four primary categories based on the genomic splice junctions from which they originate: intronic circRNAs, exon-intron circRNAs (EIciRNAs), intergenic circRNAs, and exonic circRNAs (ecircRNAs) [ 469 ]. CircRNA, in contrast to linear RNA, is a single-stranded circular transcript that lacks a 3′ poly(A) tail and a 5′ cap. Its structure is covalently closed. CircRNAs are very stable, evolutionarily conserved, and widely expressed due to their unique shape. Through specialized biogenesis mechanisms, they frequently exhibit dynamic and tissue-specific expression patterns [ 470 ].

CircRNAs as MiRNA sponges in reproductive processes

According to recent research, cells with high rates of proliferation are likely to have fewer circRNAs than cells with lower rates [ 471 , 472 ]. Because malignant cells proliferate more quickly than those in normal tissues, the expression level of circRNAs is lower in cancerous tissues [ 471 ]. CircRNA levels in primary ovarian tumors and metastatic ovarian lesions in ovarian cancer vary significantly [ 473 ]. Research has indicated that tumor samples exhibit a substantial upregulation of ciRS-7, which serves as a sponge for miR-7 [ 471 ]. Pak1, a kinase that is often triggered by DNA-damaging agents such as radiation or etoposide, is one of the oncogenes that miR-7 may control [ 474 ]. Thus, in response to stress, ciRS-7 may be upregulated in malignant cells to initiate DNA repair and prevent apoptosis [ 475 ]. Investigating the possibility that ciRS-7 is a biomarker for ovarian-related malignancies will be interesting.

According to recent studies, human peripheral whole blood contains hundreds of circRNAs, suggesting that these molecules might be easily accessible biomarkers in a body fluid that is easily accessible [ 472 ]. Zhang et al. recently discovered that circ_101222 in blood cells may be a biomarker for preeclampsia (PE) diagnosis [ 476 , 477 ]. This implies that the expression patterns of circRNAs in the blood may be used to assess reproductive health or disease states.

Numerous assisted reproductive methods subject gametes and embryos to high levels of external stress, such as freezing and thawing, in vitro maturation, fertilization, and culture. These cells need to modify their gene expression patterns in order to adapt. Since circRNAs are widely distributed in gametes and embryos, these molecules are probably impacted by these processes.

Epidermal growth factor (EGF) is secreted when LH promotes the meiotic maturation of oocytes from prophase I to metaphase II. Then, by activating its receptor, EGFR, EGF enhances oocyte maturation and encourages cumulus cell growth [ 478 ]. Since EGFR is a target of miR-7, this miRNA inhibits its synthesis [ 479 , 480 ]. By acting as a sponge for miR-7, ciRS-7 efficiently sequesters it and prevents miR-7 from performing its regulatory activities. EGFR is the target of miR-7, hence ciRS-7 may alter EGFR activity and affect oocyte maturation. Furthermore, circRNAs are crucial in controlling how cells react to a range of environmental stressors, including oxidative damage, temperature fluctuations (heat and cold shock), low temperatures, and salt stress [ 481 , 482 ]. Therefore, it is intriguing to investigate the impact of assisted reproduction on circRNA expression patterns and the importance of these gene changes.

CircRNA impact on gene expression in spermatogenesis and oocyte maturation

CircRNAs are widely expressed in spermatogenic cells, according to a recent study that found 15,101 different circRNAs in mouse spermatogenic cells [ 483 ]. CircRNAs were expressed in 5,573 spermatogonial stem cells, 5,596 primitive type A spermatogonia, 6,689 preleptotene spermatocytes, 4,677 pachytene spermatocytes, and 7,220 round spermatids, according to the cell type. Interestingly, when compared to the other cell types, round spermatids showed the greatest expression of circRNA [ 483 ]. Nevertheless, it is still unclear what the large number of circRNAs in the testis does.

Researchers examined the expression patterns of the androgen-binding protein (ABP) gene in rat testes and the cytochrome P-450 2C18 gene in human epidermis to investigate the relationship between exon skipping and circRNA production [ 484 ]. Circular transcripts of the 2C18 gene that omit certain exons have been found in the human epidermis in addition to the normal mRNAs with nine exons. Likewise, a circRNA derived from ABP gene exons 6 and 7 was discovered in rat testes, where the acceptor splice site of exon 6 is connected to the donor splice site of exon 7 [ 484 ], This implies that the creation of mRNA isoforms that omit those same exons in the testes may be connected to or impacted by the generation of circRNAs with distinct exon combinations [ 484 ]. Dong et al. used high-throughput sequencing techniques to examine the patterns of circRNA expression in human testes and seminal plasma [ 485 ]. In human testes, Dong et al. found 15,996 circRNAs, 10,792 of which were new. Of these, 1,017 genes were identified as circRNA producers for the first time, and 14,033 circRNAs linked to 5,928 host genes. Numerous host genes are linked to fertilization, sperm motility, and spermatogenesis. Additionally, the study showed that these circRNAs produced from testes are present in seminal plasma and are quite persistent at ambient temperature, most likely as a result of their interactions with proteins. Because of their stability, circRNAs in seminal plasma may be used as new, non-invasive biomarkers to evaluate male fertility [ 485 ].

The testis has the second-highest levels of circRNA expression after the brain, according to a comparative analysis of circRNA expression in the brain, liver, heart, lung, and testis [ 486 ]. This implies that testicular function is probably significantly influenced by circRNAs. The sex-determining region Y (Sry) gene produces circSry, one of the more thoroughly researched circRNAs in the testis.

Sinclair et al. initially cloned the Sry gene on the human sperm Y chromosome in 1990 [ 487 ]. Subsequent studies verified that the Sry gene is an essential regulator of sex [ 488 ]. The Sry gene’s expression pattern in the mouse testis varies according to developmental stage [ 489 ]. A crucial window between 10.5 and 12.5 days after coitum occurs during which the Sry gene is exclusively expressed in the somatic cell lineage of the developing vaginal ridge [ 488 ]. At this point, the Sry gene is translated into linear mRNA, which codes for a protein with an HMG box. As a major transcription factor, this protein is essential for controlling sex differentiation in fetuses [ 490 ]. Sry gene expression, on the other hand, is primarily linked to the first wave of spermatogenesis and the development of spherical spermatids in the adult testis. The bulk of Sry transcripts in adult testis are mostly circular RNAs, in contrast to its linear transcripts in the genital ridge [ 489 ]. It was proposed that circSry biogenesis might be caused by lengthy inverted repeats that surround the Sry gene [ 491 ]. The Sry gene’s diverse transcription patterns in the adult testis and genital ridge most likely correspond to specific functions at various developmental stages.

CircSry may be able to be translated into a protein since it has an open reading frame and a putative ATG start codon [ 489 ]. However, since there is no hard proof that circSry interacts with polysomes to promote translation, this theory is still up for debate. Moreover, whether circSry controls gene expression by acting as a miRNA sponge is also unknown. It has been proposed that elevated circSry levels in mice prevent miR-138 from attaching to its target mRNAs, suggesting a potential regulatory function [ 151 , 492 ]. Hansen et al. claim that biotin-labeled miR-138 was demonstrated to physically interact with circSry, corroborating the notion that circSry may serve as a miR-138 sponge. This shows that by blocking miR-138’s ability to attach to its target mRNAs, circSry may control gene expression [ 491 ]. Specifically, because human circSry only has one miR-138 binding site, it may not be able to function as an efficient miRNA sponge in humans. This raises the possibility that circSry has species-specific functions by suggesting that its miR-138 sponging activity may be unique to mice [ 486 , 493 ]. Indeed, circSry has a pattern of tissue-specific expression; it is mostly detected in the testis and is not detectable in the brain, liver, kidney, or spleen. Its unique involvement in testicular function and spermatogenesis is further supported by its specialization [ 489 ].

CircRNA in PCOS

A common condition that affects women of reproductive age, PCOS is characterized by metabolic and endocrine abnormalities. Multiple ovarian cysts, elevated testosterone levels (hyperandrogenemia), and persistent irregular ovulation (chronic anovulation) are important characteristics of PCOS [ 494 ]. Despite being characterized by reproductive symptoms, PCOS also causes more serious and extensive health problems that go beyond fertility. These problems frequently last well after menopause and have an impact on long-term health in general [ 495 ]. Additionally, over time, metabolic problems such as obesity, insulin resistance, type 2 diabetes, and cardiovascular illnesses are more likely to occur in patients with PCOS [ 496 , 497 ]. Even with advancements in healthcare, PCOS is still very difficult to treat efficiently. This emphasizes the necessity of fully investigating its underlying causes as well as finding more accurate diagnostic indicators and treatment approaches. The correct development and maturation of ovarian follicles and oocytes depend on follicular fluid, which is also vital for the complex communication between the oocyte and the cumulus cells that surround it. This communication is necessary for follicular development and reproductive function [ 498 ]. The complex FF environment is made up of a wide range of complex substances released by oocytes, granulosa cells, and theca cells, such as proteins, RNAs, and metabolites [ 499 – 503 ]. The critical role that circRNAs in FF play in the onset and evolution of PCOS has been brought to light by recent studies [ 504 ]. According to Huang and colleagues, miR-1294 levels increased when exosomal circLDLR was removed from the ovarian follicular fluid. Patients with PCOS produced less estradiol as a result of this increase in inhibited CYP19A1 activity [ 494 ]. More precisely, circDDX10, which is present in granulosa cells made from human follicular fluid, may be essential for regulating ovarian function. It seems to have an impact on granulosa cell maturation and death in addition to steroid hormone synthesis [ 505 ]. It has been demonstrated that several circRNAs, such as circASPH, circLDLR, and circPUM1, are crucial for the control and advancement of PCOS [ 494 , 506 , 507 ]. It is still unknown how many circRNAs have a role in the development of PCOS. However, circRNAs’ stability, resistance to degradation, and prevalence in ovarian tissue underscore their encouraging potential as trustworthy PCOS diagnostic biomarkers [ 508 , 509 ].

CircRNAs as potential biomarkers in reproductive disorders

Accurate illness diagnosis requires the application of sophisticated biomarker finding approaches. CircRNAs have garnered a lot of attention lately because of their distinctive qualities, which include tissue-specific expression patterns, prolonged stability, and high abundance, which make them excellent candidates for use as disease biomarkers. In the past, studies looked at the stability of miRNAs and other RNA transcript sections as biomarkers. The discovery of circRNAs, however, has caused attention to turn toward investigating these molecules using RNA studies in order to assess their accuracy and dependability as diagnostic indicators [ 510 , 511 ]. CircRNAs have great potential as trustworthy biomarkers for a number of illnesses, such as cancer, neurological disorders, and cardiovascular diseases, because of their role in both transcriptional and post-transcriptional control. Their release from cells into the circulation, which offers easily accessible targets for biomarker development, is primarily responsible for this potential. Furthermore, the utility of exosomes is increased by the presence of circRNAs within them, providing a new, least intrusive method of cancer diagnostics [ 512 ]. CircRNAs found in circulating exosomes in the blood are a new and trustworthy class of biomarkers in patients with colorectal cancer (CRC) [ 512 ].

The study of circRNAs in human illnesses has become a major and fast increasing subject. Different illnesses demonstrate diverse patterns of circRNA expression, with certain circRNAs showing upregulation while others are downregulated. CircRNAs have garnered a lot of interest as possible therapeutic agents because of their function in controlling gene expression. Numerous circRNAs are now being studied or used as therapeutic targets across a range of medical diseases, and researchers are actively investigating further circRNAs that may be used as therapeutic targets. Furthermore, it has been demonstrated that certain circRNAs that function as tumor suppressors may be transformed into therapeutic agents for the treatment of cancer [ 513 ]. Functional research that alters circRNA levels using methods like inhibition or overexpression is crucial to fully investigate the therapeutic potential of these molecules. CircRNAs may be produced and inserted into cells using techniques like splint ligation or self-splicing introns, which enable scientists to precisely assess their biological functions [ 514 – 516 ]. Using overexpression plasmids designed to carry the desired circRNA sequence is a technique for increasing circRNA levels [ 517 ].

CircRNAs are more stable than many other RNA types because of their entirely closed circular shape. CircRNAs are especially well-suited for usage as trustworthy biomarkers in upcoming studies and therapeutic applications because of their innate durability [ 518 – 521 ]. CircRNAs have tremendous promise as therapeutic agents across a number of illnesses, including neurological disorders, cardiovascular ailments, and malignancies, emphasizing their vast potential in medical therapy [ 522 – 525 ]. CircRNAs’ role in the initiation and spread of cancer has been the subject of an increasing number of studies recently [ 526 – 528 ]. CircRNAs have been linked in several studies to different forms of cancer. Interestingly, it has been discovered that certain circRNAs derived from the tumor suppressor gene FBXW7 encode proteins that decrease the stability of the carcinogenic c-Myc protein [ 529 ]. Two distinct families of circRNAs, circHIPK3 and circDOCK1, are important regulators of cell division and biomarkers for the identification of cancer [ 479 , 530 ]. CircRNAs, for instance, are substantially less abundant in tumor tissues of colorectal and ovarian malignancies than their comparable linear RNA isoforms [ 531 ]. There was a pronounced inverse relationship between the ratio and the rate of cancer cell growth. Furthermore, in contrast to healthy persons, patients with colon cancer displayed distinct patterns of circRNA expression in their peripheral blood exosomes [ 532 ]. Although their precise function in cancer is yet unknown, these circRNAs have potential as biomarkers for the detection or monitoring of endometrial carcinoma (EC). The specific effects of circRNAs on EC have not yet been studied, despite evidence linking them to tumor growth and progression.

Noncoding RNAs as biomarkers in infertility diagnosis

The process of identifying ncRNA biomarkers begins with the careful collection of biological samples from both infertile patients and healthy controls. Common sources include blood, serum, follicular fluid, seminal plasma, and endometrial or testicular tissue. The quality and relevance of these samples are crucial for downstream RNA extraction and analysis. Different approaches have been used to identify and validate ncRNAs involved in reproductive disorders, including computational prediction, gene expression profiling, and next-generation sequencing (NGS). These methods enable the detection of novel ncRNAs and the characterization of their expression patterns in healthy versus infertile individuals. Integration of transcriptomic data with bioinformatic tools further aids in identifying potential ncRNA biomarkers (Fig. 3 ). Fig. 3 Workflow for Identifying ncRNA Biomarkers in Infertility

A schematic overview outlining the main stages of ncRNA biomarker discovery in infertility research, including sample collection, RNA extraction, profiling, bioinformatics analysis, clinical correlation, and validation in independent cohorts.

Potential of NcRNAs as non-invasive biomarkers in semen, follicular fluid, and blood

Semen

Semen Extracellular Vesicles (sEVs) are characterized by a complex array of proteins and a high concentration of sphingomyelin and cholesterol. These vesicles also contain RNA molecules that may be transported to target cells, where they alter and affect biological processes [ 533 – 535 ]. This class of RNA includes a wide variety of non-coding regulatory RNAs as well as messenger RNAs mRNAs, which transfer genetic information from DNA to the translational machinery for protein synthesis. These comprise long and small ncRNAs, which are crucial for regulating gene expression, chromatin remodeling, RNA splicing, and other vital cellular regulatory processes but do not produce proteins [ 534 ].

A unique and functionally significant repertoire of sncRNAs, which are usually 20–100 nucleotides long, is abundant in sEVs. Through intricate epigenetic alterations and post-transcriptional regulatory networks, these molecular entities play crucial roles in coordinating gene expression, eventually impacting a wide range of cellular and developmental processes [ 536 ]. sncRNAs are a broad category that includes a wide range of RNA types, such as endo-siRNAs, piRNAs, and miRNAs, all of which are important regulatory factors in the growth and operation of germ cells. Furthermore, more recently identified classes like ribosomal RNA-derived small RNAs (rsRNAs) and transfer RNA-derived small RNAs (tsRNAs) have surfaced; however, their specific roles in reproductive biology and fertility are still being studied and are not fully understood [ 537 ]. The two most prevalent sEVsncRNAs in semen are miRNAs (21%) and tsRNAs (16%) [ 538 ]. Semen contains sEVs with a distinct sncRNA profile that is not present in sEVs from other fluids [ 538 ].

As mentioned before, sEVs come from different parts of the male reproductive system. The chemical cargo that these sEVs carry is representative of the cellular source, and the quantity and makeup of these molecules may be used as markers of the health and integrity of the parent cells. The dysregulation of gene expression linked to pathological illnesses affecting male reproductive organs, such as spermatogenesis abnormalities and prostate cancers, has been linked to certain subtypes of sncRNAs, especially miRNAs [ 329 , 539 ]. The idea that studying the tiny RNA cargo inside sEVs provides important information about the pathological state of male reproductive organs is supported by these features. Delineating the baseline expression patterns of small RNA molecules throughout the many organs of the male reproductive system is essential because of the tissue-specific heterogeneity in these molecules’ expression profiles. Accurately interpreting sncRNA signals in semen-derived sEVs and expanding their use as possible non-invasive biomarkers for urogenital diseases requires this fundamental understanding.

Follicular

A major factor in determining the success of a pregnancy, embryo quality is primarily assessed using morphological evaluation criteria, which usually include traits like the quantity of blastomeres and the degree of cytoplasmic fragmentation [ 540 , 541 ]. However, the existing morphological grading system lacks standardized, clinically proven objective criteria and is intrinsically subjective, largely depending on the knowledge and interpretation of embryologists. FF, a dynamic and biochemically rich milieu that is crucial for oocyte development, becomes a useful source of molecular information in this setting. It includes a wide range of bioactive compounds that are released by the oocyte itself, as well as by the granulosa, cumulus, and theca cells that surround it. These molecules reflect the follicle’s physiological condition and the oocyte’s capacity for development [ 542 – 544 ]. According to earlier research, some miRNAs in FF are linked to the quality of human embryos [ 545 ]. They haven’t, however, talked about how miRNAs and pregnancy outcomes are related.

The primary role of microRNAs miRNAs, a type of tiny, single-stranded non-coding RNAs with an average length of 22 nucleotides, is the post-transcriptional control of gene expression [ 546 ]. The fact that miRNAs are found in a variety of body fluids, such as follicular fluid, urine, and peripheral blood, indicates their broad physiological and perhaps diagnostic importance [ 547 ]. Particularly when enclosed within membrane-bound nanovesicles like EVs, such as exosomes, which shield them from enzymatic breakdown and promote intercellular communication, miRNAs show remarkable stability within these biological fluids [ 534 ]. EVs are known to carry a variety of cargo, including proteins, messenger RNAs mRNAs, and miRNAs, all of which are actively secreted into the extracellular environment. Via transporting their chemical contents to destination cells, these vesicles enable intercellular communication by modifying signaling pathways and biological processes [ 534 , 548 ]. The functional importance of intracellular communication mediated by EVs has been studied by several researchers. MicroRNAs found in follicular fluid-derived EVs (FF-EVs) have recently been identified as prospective indicators for reproductive health and illness in addition to being important mediators of intercellular communication [ 549 ]. Apart from microRNAs, another well-known family of tiny non-coding RNAs is P-element-induced wimpy testis piRNAs. These RNAs, which range in length from 21 to 35 nucleotides, work in tandem with PIWI proteins to control gene expression and preserve genomic integrity [ 30 , 550 ]. By managing the silence of transposable elements and regulating gene expression, piRNAs play a critical role in protecting the germline in mammalian oocytes and early embryonic stages, maintaining genomic integrity and guaranteeing appropriate developmental progression [ 551 , 552 ]. A very sensitive single-cell small RNA sequencing method was recently created by Yang et al. to thoroughly profile short non-coding RNAs in human oocytes and early-stage embryos [ 553 ]. Previous studies have shown that zebrafish female infertility is caused by abnormalities in the piRNA pathways, underscoring the critical role piRNAs play in reproductive function [ 554 ]. Based on these results, it is logical to speculate that piRNAs also play important roles in the human germline, notably in FF, supporting both genomic integrity and reproductive activities.

Using FF-EVs, they investigate the small non-coding RNA (ncRNA) content as a possible predictive biomarker for pregnancy outcomes in assisted reproductive technology (ART). FF-EVs were effectively extracted, and a particular panel of small ncRNAs, miR-16-2-3p, miR-378a-3p, and miR-483-5p, that reliably differentiate samples linked to a successful pregnancy was discovered. Furthermore, these potential miRNAs’ functional investigations demonstrate their role in embryo quality and follicular development. These findings provide important new information on the molecular processes that underlie folliculogenesis and oocyte maturation.

Lastly, functional studies were performed to assess the connection between follicular development and the discovered miRNAs. First, seven differently expressed miRNAs (miR-16-2-3p, miR-146a-5p, miR-204-3p, miR-378a-3p, miR-483-5p, miR-1246, and miR-1290) were used to identify their possible biological functions using the miRSystem algorithm. Three miRNAs, miR-16-2-3p, miR-378a-3p, and miR-483-5p, were given priority from this group according to their anticipated interactions with 189 target mRNAs found by the miRSystem study. To better contextualize these associations, then included a dataset of 640 mRNAs that had been previously associated with embryo quality in prior studies [ 555 ]. Scientists narrowed the dataset to a targeted group of seven genes by combining the 189 mRNAs linked to the chosen miRNAs with the 640 mRNAs previously found to be related to embryo quality. Important regulators of embryonic development, including members of the SOX and RHO gene families, were included in this reduced gene collection. These seven miRNAs were shown to have considerable dysregulation, according to gene ontology (GO) analysis, which also highlighted the BMP signaling pathway as a crucial regulator of oocyte development. All of these results point to the possibility that the miRNAs contained in FF-sEVs, small extracellular vesicles generated from follicular fluid, may be crucial in regulating follicular maturation and embryo quality.

Blood

More than 210,000 distinct species of lncRNA have been found, in contrast to the about 2000 human miRNAs [ 556 ]. Nevertheless, little is known about this family of non-coding RNAs. One notable exception is Prostate Cancer Antigen 3 (PCA3), a urine biomarker that has been thoroughly investigated in individuals with prostate cancer and may have more specificity than the traditional Prostate-Specific Antigen (PSA) test [ 557 , 558 ]. Although the evidence for this claim comes from a smaller patient group, blood levels of MALAT1 have also been proposed as a possible biomarker for prostate cancer. Furthermore, five lncRNAs were shown to have differential expression in plasma samples from patients with multiple myeloma (MM) and chronic lymphocytic leukemia compared to healthy controls: TUG1, LincRNA-p21, MALAT1, HOTAIR, and GAS5 [ 559 , 560 ]. Patients with hepatocellular carcinoma have been found to have higher plasma levels of the long non-coding RNA HULC than healthy controls [ 561 ]. When comparing the saliva of patients with oral squamous cell carcinoma to that of healthy controls, six lncRNAs were found to express differently, suggesting that they may be useful in differentiating metastatic cases [ 562 ]. lncRNAs generated from mitochondria have also been suggested as urine biomarkers for bladder cancer monitoring and diagnosis [ 563 ]. Compared to healthy controls, gastric cancer patients had considerably higher plasma levels of the long non-coding RNA H19 [ 564 ]. Circulating levels of the long non-coding RNA LIPCAR are predictive indicators for survival outcomes in heart failure patients, not just in cancer [ 565 ]. Along with long non-coding RNAs, ovarian cancer patients’ blood has been shown to have higher amounts of the small nuclear RNA (snRNA) U2, which has been linked to treatment response. Additionally, it was shown that individuals with non-small cell lung cancer (NSCLC) had higher levels of six short nucleolar RNAs (snoRNAs) in their plasma [ 566 , 567 ]. Studies examining the existence or function of piRNAs or other non-coding RNA types in bodily fluids have not yet been published.

Challenges in translating NcRNA biomarkers into clinical practice

Despite the great potential of ncRNAs as biomarkers for reproductive diseases, a number of obstacles prevent their practical application. The primary cause of variability that may jeopardize the precision and repeatability of ncRNA detection is the absence of established procedures for sample collection, processing, and RNA extraction. Furthermore, the creation of reliable diagnostic standards is made more difficult by the significant variation in ncRNA expression among various people, tissue types, and disease stages. Another obstacle to ncRNAs’ clinical use is their tissue- and context-specificity, which makes comprehensive functional validation necessary to precisely define their biological activities. Furthermore, the present findings’ wider relevance and validity are limited by the dearth of extensive, multicenter clinical research. Last but not least, creating assays that are dependable, reasonably priced, and extremely sensitive for regular clinical use is still a significant issue. To fully realize the promise of ncRNAs as diagnostic and therapeutic tools in the management of infertility, these challenges must be addressed ( Table 4 ) . Emerging therapeutic strategies targeting ncRNAs, including miRNA-based therapies, lncRNA modulation, and exosome-mediated delivery, offer promising avenues to overcome current obstacles and improve reproductive outcomes (Fig. 4 ). Fig. 4 Therapeutic Strategies Targeting ncRNAs for Infertility Table 4 Multi-fluid NcRNA atlas reveals fertility biomarkers and translational diagnostic frontiers Fluid ncRNA Types Fertility Roles Advantages Limitations/Challenges Key Findings Refs Semen miRNAs, tsRNAs, piRNAs, rsRNAs, endo-siRNAs sEVs regulate genes, support spermatogenesis, and carry fertility markers Easy sampling; reflects prostate–testis status Mixed origin; unknown functions; high variability; needs standardized sEV isolation miRNAs (~ 21%), tRNA fragments (~ 16%); miR-34c-5p dysregulated in infertility [ 537 ] Follicular Fluid miRNAs (miR-483-5p, miR-16-2-3p, miR-378a-3p), piRNAs Indicates follicular health, predicts oocyte/embryo viability, and modulates BMP/RHO High diagnostic value (AUC ≈ 0.96); sEV-stable Invasive collection; small cohorts; requires pure sEVs and target validation Listed miRNAs associate with pregnancy success and embryo quality [ 568 ] Blood lncRNAs (HULC, GAS5, HOTAIR, MALAT1), snRNAs, snoRNAs Systemic and reproductive biomarkers Stable, minimally invasive, long-term monitoring Low signal/noise; poor tissue specificity; reproductive roles unclear MALAT1 linked to infertility & prostate cancer; H19 to reproductive disorders [ 14 , 569 – 576 ]

Overview of emerging ncRNA-targeted therapies in reproductive disorders, highlighting miRNA mimics and inhibitors, lncRNA modulation via CRISPR/Cas9 and antisense oligonucleotides, and exosome-mediated delivery systems for targeted treatment of infertility [ 577 ]. Optional strategies include nanoparticle use, safety considerations, and combination with hormonal therapies [ 578 ].

Future perspectives and challenges in infertility

Progress in ncRNA-Targeted Pharmacotherapy

In the last ten years, the view of ncRNAs has evolved from being considered “transcriptional noise” to a diverse array of viable therapeutic targets in reproductive medicine. MiRNAs, lncRNAs, and circRNAs regulate gene expression programs that control gametogenesis, embryo implantation, and early embryonic development [ 162 ]. The disruption of these precisely regulated networks is now acknowledged as a causative element in both male and female infertility, leading to vigorous attempts to develop medications that either block pathogenic ncRNAs or restore protective ones. Two primary tactics prevail in this burgeoning domain. Loss-of-function methodologies comprising antisense oligonucleotides (ASOs), siRNAs, and chemically stabilized antagomirs aim to inhibit disease-promoting non-coding RNAs, such as over-expressed microRNAs that hinder spermatogenesis or disrupt endometrial receptivity. In contrast, gain-of-function therapies seek to reintroduce advantageous non-coding RNAs using synthetic mimics, designed circular RNA scaffolds, or expression vectors that improve oocyte competence or embryo survivability. Each method requires precise sequence specificity and sustained action in gonadal or peri-implantation tissues. Delivery technology has emerged as the essential facilitator [ 579 ]. Lipid-based nanoparticles (LNPs), confirmed by mRNA vaccinations, currently function as modular carriers for ncRNA therapeutics, providing adjustable size, surface charge, and tissue specificity. Recent developments include ionizable lipids, biodegradable linkers, and reproductive-tissue-targeting ligands that penetrate biological barriers, including the blood–testis and blood–follicle interfaces. Conjugated oligonucleotides, which include the chemical linkage of therapeutic RNA to targeting moieties such as N-acetyl galactosamine or peptide ligands, demonstrate enhanced absorption by Sertoli cells and endometrial epithelium in preclinical studies [ 580 ]. Exosome-based systems, using natural vesicles either from follicular fluid or seminal plasma, provide a biocompatible method for the targeted transport of non-coding RNA. Notwithstanding these advancements, significant difficulties persist. Reproductive organs display distinct immune surveillance; activation of the innate immune system may hinder implantation or spermatogenesis. Off-target hybridization poses a danger of dysregulating unrelated transcripts, and long-term germline consequences must be thoroughly eliminated. Consistency in manufacturing, stability of the cold chain, and scalable Good Manufacturing Practice (GMP) production are all essential for use in assisted reproduction clinics. Future advancements will likely depend on integrated design pipelines that combine high-resolution transcriptomics with artificial intelligence-driven sequence optimization, facilitating predictive modeling of off-target profiles and delivery efficacy. Current early-phase studies in several therapeutic domains, including hepatic and ocular RNA therapeutics, provide a regulatory framework that may be used for reproductive medicine. Collectively, these advancements establish ncRNA-targeted treatments as a viable next frontier for addressing hitherto resistant types of infertility, integrating basic RNA biology with precision reproductive medicine [ 162 ].

Incorporation of ncRNA Biomarkers in Tailored Reproductive Medicine

The emergence of high-throughput sequencing and precise RNA quantification has converted non-coding RNAs from mere mechanistic curiosity into viable biomarkers in reproductive medicine. NcRNAs comprising miRNAs, lncRNAs, circular RNAs, tRNA fragments, and sncRNAs are consistently found in biofluids (such as serum, plasma, follicular fluid, and uterine fluid) and tissues, with their expression profiles mirroring the fundamental reproductive physiology and pathology. Due to their stability, tissue specificity, and sensitivity to disturbance, they provide significant potential for non-invasive diagnostics, prognostics, and patient stratification [ 581 ]. Recent investigations have validated ncRNA markers in infertile populations. Senousy et al. developed a serum panel of TUG1/miR-141 and TUG1/miR-483 that differentiates NOA and severe oligozoospermia (SO) from healthy males, with reported AUCs of 0.93 and 0.972, respectively [ 181 ]. Their correlations with hormonal and clinical markers further substantiate their translational potential. In a similar vein, Salman et al. assessed NEAT1 and miR-34a in serum as biomarkers for non-obstructive azoospermia and severe oligospermia, revealing diagnostic distinction and associations with sperm parameters [ 178 ]. In endometrial settings, Xu et al. discovered four serum tsRNAs associated with endometrial receptivity, demonstrating that one, tsRNA-35:73-Asp-GTC-1, targets Wnt3 and affects decidualization in vitro [ 582 ].

Ethical Considerations and Regulatory Challenges in ncRNA-Based Infertility Therapy

The rapid progression of ncRNA therapies from basic research to clinical application demands equally rapid advances in ethical foresight and regulatory design. The rapid progression of ncRNA treatments from basic research to clinical application necessitates corresponding improvements in ethical foresight and regulatory frameworks [ 583 ]. Intervening in ncRNA signaling during gametogenesis or early embryogenesis beyond mere molecular manipulation; it encompasses generational boundaries, personal liberty, and societal trust. Although the reviewer praises the incorporation of ethical inquiries, this area needs more profound, proactive consideration as the technologies near practical implementation [ 584 ].

Intergenerational epigenetic inheritance vs. molecular temporality

A primary conflict is that although ncRNA-based therapies do not permanently alter genomic sequences, their ability to reconfigure regulatory networks might result in heritable epigenetic “scars.” Recent in vitro reconstruction of human germline epigenetic reprogramming has shown the sensitivity of germ cell chromatin to minor RNA alterations [ 585 ]. The potential for short-lived ncRNA modification to transmit between generations requires significant care. Ethical frameworks must include progressive exposure procedures, beginning with experiments limited to somatic or late-preimplantation material, followed by stringent multigenerational animal models before any germline interaction. Longitudinal registries, preferably including a minimum of two generations, should be incorporated into trial design [ 586 ].

Informed consent under speculative risk environments

NcRNA treatments intrinsically include probabilities and uncertainties; outcomes are not certain. Prospective parents must traverse “speculative risk landscapes,” where the extent and reversibility of off-target impacts are not well delineated. Conventional consent forms must transform into dynamic, interactive documents enhanced with choice aids, visual risk simulations, and layered explanations. Due to the nonconsenting nature of future children as stakeholders, a specialized ethical evaluation is required to evaluate the adequacy of consent mechanisms in representing their interests. Moreover, the distinction between treatment and enhancement becomes especially slippery; policies should forbid elective trait optimization and define clear boundaries of acceptable use.

Epistemic justice, accessibility, and reproductive equity

Emerging technologies often exacerbate inequities. During the first adoption phase, ncRNA therapies inevitably costly and technologically complex may be confined to prestigious fertility clinics, hence intensifying reproductive disparities. Justice necessitates that trials include socioeconomically diverse individuals and provide inclusive access from the beginning (e.g., sliding scale pricing, public financing, technology transfer to under-resourced environments). Institutional review boards and funding organizations should impose “justice impact” statements that predict inequities and need mitigation actions.

Regulatory framework for epigenetic therapies

NcRNA-based epigenetic therapies occupy a regulatory gray area: they are neither traditional small-molecule drugs nor permanent genomic modifications, but they may reconfigure cellular networks in ways that resonate throughout generations. Their ephemeral chemical trace conceals the capacity to establish lasting, inheritable epigenetic changes, indicating that current paradigms for gene therapy, RNA therapies, and assisted reproduction only include portions of the risk landscape. To address this disparity, contemporary policy discussions propose a complete regulatory framework for “epigenetic therapeutics,” an oversight system as inventive as the research it regulates [ 587 ]. This method would selectively include the evidential criteria of medication approval, the containment protocols of gene-drive research, and the equality principles of reproductive medicine, while implementing precautions specifically designed for epigenome editing. Essential components would encompass tiered oversight linked to germline proximity, ensuring that somatic applications adhere to an efficient RNA-drug protocol, while any intervention with even a slight possibility of germline transmission necessitates the most rigorous international scrutiny, public engagement, and immediate data transparency [ 588 ]. It would require multigenerational monitoring, necessitating registries that document clinical outcomes and epigenetic markers across a minimum of two descendant cohorts; establish a globally interconnected adverse-event reporting system to prevent jurisdictional “shopping”; and implement justice audits that assess affordability, technology transfer, and representation of under-resourced populations before the enrollment of any patient. Dynamic consent platforms’ interactive, perpetually updatable digital documents would replace static paper forms, enabling participants to reassess their decisions as new information becomes available. By integrating scientific, ethical, and societal elements into a cohesive framework, ncRNA therapeutics would be regarded not merely as an incremental drug class but as a distinct category of biomedical intervention, necessitating regulatory innovation commensurate with its transformative potential and ensuring that progress is characterized by transparency, intergenerational accountability, and global legitimacy [ 589 ].

Deliberative audiences and democratic supervision

Technical safety is a necessary but inadequate basis for legitimacy. In the first stages of development, public involvement via citizen juries, participatory workshops, and internet platforms may reveal values, concerns, and social norms. Clarity about risk, reward, uncertainty, and value-laden decisions is essential. Incorporating a “social license to operate” entails that patients, ethicists, advocacy organizations, and regulators together bear responsibility, rather than just serving as passive users of technology. By integrating ethical considerations into the translational narrative, the field can progress from molecular potential to socially anchored implementation, ensuring that ncRNA-based infertility treatments are developed with scientific rigor, respect for future generations, equity, and democratic legitimacy. Future

Research Directions: Integrating ncRNAs with CRISPR and Advanced Gene-Editing Technologies

The amalgamation of non-coding RNA (ncRNA) biology with precision genome editing constitutes one of the most active areas in reproductive medicine. Instead of only functioning as downstream regulators, ncRNAs are progressively seen as programmable elements inside highly adaptable gene-engineering systems. This conceptual transformation regarding ncRNAs as both biological signals and modular components facilitates the development of medicines that are corrective, regulatory, and attuned to the unique environment of the reproductive system.

Data from Sophisticated Pre-clinical Models

An expanding corpus of advanced pre-clinical research indicates that the integration of ncRNAs with CRISPR technology is substantiated beyond mere theory. Lipid-nanoparticle delivery of CRISPR/Cas9 in mouse germline models has demonstrated correction of infertility-linked alleles in mouse germline models, producing fertile offspring while maintaining genomic stability in follow-up generations [ 590 ]. Experiments involving large animals, such as porcine ovarian-insufficiency models, have integrated Cas13 RNA-targeting enzymes with synthetic microRNAs to rectify hormone signaling deficiencies and reinstate folliculogenesis, providing a direct insight into therapeutic potential in species with reproductive physiology akin to that of humans [ 591 ]. Concurrent investigations using human testicular organoids’ three-dimensional preparations that replicate the seminiferous tubules’ microenvironment have shown that piRNA-guided Cas13 complexes may inhibit transposon activity, thereby preserving genomic integrity during spermatogenesis. These results advance the science beyond observational biology to intentional functional engineering of reproductive organs, paving the way for meticulously controlled translational investigations [ 592 ].

Developing Clinical Pathway

Despite the stringent regulatory oversight of heritable human germline editing, related therapeutic initiatives are establishing a foundation for potential reproductive uses. Initial studies employing lipid-nanoparticle–delivered CRISPR base editors in metabolic and hematologic disorders have produced significant data about long-term safety, immunological tolerance, and in vivo editing efficacy information pertinent to ovarian and testicular targets. Similarly, Cas13-mediated RNA editing experiments for mitochondrial diseases are exhibiting prolonged RNA knockdown without observable off-target consequences, offering clinical validation for transitory, programmable non-coding RNA modification in human tissues. These activities provide an essential translational bridge: the manufacturing standards, pharmacokinetics, and patient-monitoring procedures developed in these somatic contexts may be swiftly adopted whenever reproductive indications get ethical and legal approval for clinical research [ 593 , 594 ].

Programmable “Smart-Editor” Architectures

Next-generation genome editors are advancing from singular-function nucleases to intricate molecular machinery capable of dynamic modulation. Novel designs incorporate long or short ncRNA scaffolds directly into guide RNAs or donor templates, therefore attracting chromatin remodelers, RNA-binding proteins, and DNA repair factors to targeted genomic loci. This technique enables researchers to direct repair results towards desired alleles, reduce mosaicism, and precisely adjust gene expression in real time. After successful DNA repair, inducible synthetic microRNAs or antisense RNAs may further modulate transcriptional activity to preserve the intricate hormonal equilibrium necessary throughout gametogenesis and early embryonic development. This dual-layer control, accurate genomic repair, combined with modifiable post-transcriptional modulation, reconceives CRISPR not only as a singular editing occurrence but as a dynamic, responsive system capable of ongoing regulation inside reproductive organs [ 595 ].

Innovations in Computation and Delivery

Equally revolutionary are advancements in computational design and precise delivery. Foundation-model methods now use chromatin accessibility, three-dimensional genomic architecture, and ncRNA interactomes to estimate guide-RNA efficacy and off-target hazards at almost single-cell resolution. This computational capability allows tailored editing tactics before the initiation of any laboratory experiment. In terms of delivery, reproductive-tissue-specific carriers engineered lipid nanoparticles, biodegradable polymer micelles, and exosome-mimetic vesicles have shown sustained release of Cas13 and ncRNA cargos in pre-clinical primate studies, with no significant innate-immune activation observed during the study period. Collectively, these digital and material advancements minimize experimental trial-and-error, expedite development timetables, and improve the accuracy of reproductive gene therapy [ 596 , 597 ].

Significant Obstacles and Moral Obligations

Notwithstanding significant advancements, substantial obstacles persist. Maintaining consistent production of synthetic ncRNA modules during consecutive germline divisions, identifying and addressing off-target occurrences across multi-omic layers, and preventing detrimental interactions with endogenous RNA networks are critical for secure clinical translation. A rigorous ethical framework is also essential: clear consent procedures, extensive long-term monitoring, and worldwide regulatory collaboration must be established before any responsible effort at heritable intervention. In the absence of these protections, even the most sophisticated molecular techniques cannot be ethically used [ 598 , 599 ]. These ethical considerations align with international guidance, including the 2021 World Health Organization recommendations on human genome editing, which emphasize global coordination and long-term oversight.

Collectively, these advancements convert the amalgamation of ncRNAs and CRISPR from a far-off ambition into a swiftly evolving scientific domain. By integrating programmable RNA modules with adaptive genome editors and using machine-learning–informed design, reproductive medicine is set to go well beyond mere single-gene repair. The ultimate objective is the dynamic reprogramming of whole regulatory networks, allowing highly personalized approaches to restore fertility, avert genetic diseases, and protect reproductive health for future generations [ 600 ].

Fig. 5 outlines future directions in ncRNA research for reproductive medicine, highlighting advances such as personalized fertility treatments based on ncRNA profiles, multi-ncRNA biomarker panels, single-cell sequencing approaches, AI-driven predictions, ncRNA editing technologies, and the translation of these findings into clinical trials

Figure 5 . Future Directions for ncRNA Research in Reproductive Medicine. Prospective advances in the application of ncRNAs for infertility, including personalized medicine based on ncRNA profiling, multi-ncRNA biomarker panels, single-cell sequencing to elucidate cell-specific functions, AI and machine learning for predictive modeling, ncRNA editing tools for epigenetic modulation, and the ongoing translation of research into clinical trials.

Conclusion

Infertility is a complex condition influenced by genetic, epigenetic, and environmental factors. Increasing evidence now establishes non-coding RNAs (ncRNAs) such as microRNAs, long non-coding RNAs, PIWI-interacting RNAs, and novel circular RNAs as pivotal orchestrators of this intricate system. In addition to their established functions in gametogenesis, hormone regulation, and early embryonic development, ncRNAs are increasingly acknowledged as dynamic sensors of reproductive stress, adept at integrating metabolic signals, environmental influences, and intergenerational epigenetic information into precise gene-regulatory frameworks. This review highlights how these compounds connect molecular biology with therapeutic application. Consistent ncRNA fingerprints in readily obtainable specimens’ seminal plasma, follicular fluid, endometrial secretions, and circulating extracellular vesicles provide a foundation for minimally invasive diagnostics and real-time surveillance of reproductive health. Synthetic mimics, antagomirs, and RNA-guided delivery methods signify a new epoch in ncRNA-based treatments, focused on restoring fertility by reconfiguring impaired regulatory networks. Future clinical translation will need more than just incremental validation. Multi-omics profiling integrated with machine-learning analytics, spatial transcriptomics of reproductive organs, and longitudinal cohort studies across varied populations are crucial for elucidating the temporal dynamics of ncRNA expression and their causal relationships with fertility outcomes. The amalgamation of these data with personalized reproductive medicine may facilitate predictive modeling, prompt intervention, and customized therapy design. This research positions ncRNAs as both monitors and mediators of reproductive function, redefining infertility as a dynamic, reversible condition rather than a fixed illness. Realizing this ambition requires interdisciplinary collaboration encompassing fundamental RNA biology, bioengineering, clinical trial design, and ethical oversight, ensuring that ncRNA-based diagnostics and therapeutics transition from experimental insights to routine clinical use.

Publisher’s Note

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Fatemeh Ziyadloo, Mahsa Rezaeian Zadeh, Kasra Allaei Rouzbahani and Maryam Kazemi contributed equally to this work.

Acknowledgements

The authors thank their respective institutions for providing access to academic resources and databases used in preparing this review. We acknowledge ChatGPT for the improvement of the writing.

Authors’ contributions

All authors contributed to the conceptualization and design of the review. AmirHossien Borji and Cena Aram conducted the literature search and initial drafting. Fatemeh Ziyadloo, Mahsa Rezaeian Zadeh, Kasra Allaei, and Maryam Kazemi critically reviewed and synthesized the literature. Maryam Barancheshmeh and Ali Alishvandi provided insights into therapeutic innovations. Abdolreza Daraei supervised the project, edited the manuscript, and finalized the content. The Figure was created by Maryam Barancheshmeh and Ali Alishvandi. All authors reviewed and approved the final manuscript.

Funding

This work received no specific funding from any public, commercial, or not-for-profit agencies. The authors conducted this review as part of their academic and research activities.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Conflicts of interest

The authors (AmirHossien Borji, Cena Aram, Fatemeh Ziyadloo, Mahsa Rezaeian Zadeh, Kasra Allaei, Maryam Kazemi, Maryam Barancheshmeh, Ali Alishvandi, and Abdolreza Daraei) declare no conflicts of interest that could influence the content of this review article.

Ethics approval and consent to participate

As this is a review article based on previously published studies, no ethical approval or informed consent was required.

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