In recent years, the intricate molecular machinery governing ovarian function has garnered significant attention, revealing complexities that go beyond traditional genetic and hormonal paradigms. One of the most compelling developments arises from the study of circular RNAs (circRNAs), a novel class of endogenous non-coding RNAs with unique covalently closed loop structures. These circRNAs have emerged as crucial players in the regulation of follicular dynamics, offering transformative insights into two predominant female reproductive disorders: polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). These disorders, while distinct in their etiologies and clinical manifestations, share a common pathological nexus rooted in abnormal follicular growth and development. Recent cutting-edge research elucidates how circRNAs influence these conditions at molecular and cellular levels, heralding promising prospects for diagnostics and therapeutic interventions.
Polycystic ovary syndrome (PCOS) remains one of the most prevalent endocrine disorders affecting women of reproductive age, characterized by a triad of ovarian polycystic morphology, hyperandrogenism, and systemic insulin resistance. This constellation drives a cascade of clinical sequelae, including menstrual irregularities, infertility, and a heightened risk for metabolic syndrome. The pathophysiology of PCOS pivots heavily on dysregulated folliculogenesis, where abnormal follicle development precipitates hormonal imbalances and metabolic derangements. Emerging data implicate circRNAs as pivotal molecular regulators in this context, capable of modulating gene expression through competing endogenous RNA (ceRNA) networks that act as sponges for microRNAs (miRNAs), thus fine-tuning granulosa cell proliferation, apoptosis, and steroidogenesis.
A striking exemplar of circRNA function in PCOS is circ_0008285 located in follicular fluid-derived exosomes, which orchestrates lipid metabolism via the miR-4644/LDLR axis. This modulation of lipid homeostasis addresses a fundamental metabolic disturbance intrinsic to PCOS pathogenesis. Beyond lipid metabolism, circRNAs such as circ_0043533 have been shown to sequester miR-1179, relieving its repressive effects on ovarian granulosa cell viability and apoptosis, directly impacting follicular maturation. These molecular interactions elucidate a tightly regulated network where circRNAs act as master controllers, integrating metabolic signals with follicular development. Another notable circRNA, circ_FURIN, has been implicated in the repression of myosin 1 (MTM1), linking cytoskeletal dynamics and muscle metabolism to ovarian pathology, further underscoring the multifaceted roles of circRNAs in PCOS.
The dysregulation of steroid hormone synthesis is a hallmark of PCOS, and studies reveal circ_0043532 as a ceRNA for miR-1270 that elevates CYP19A1 expression, a critical aromatase enzyme in estrogen biosynthesis. This regulation not only affects local follicular endocrine functionality but also extends to systemic hormonal imbalances characteristic of PCOS. Collectively, these findings position circRNAs as central nodes within the molecular circuitry of PCOS, with broad implications for biomarker discovery and targeted therapeutics, offering potential routes to mitigate ovarian dysfunction and associated metabolic disorders.
In contrast to PCOS’s hyperactive follicle environment, premature ovarian insufficiency represents a pathophysiological condition marked by premature depletion or impaired maturation of the ovarian follicular reserve, culminating in reduced estrogen production and elevated gonadotropin levels. Clinically, POI manifests as menstrual irregularities, infertility, and increased susceptibility to osteoporosis and cardiovascular disease, underscoring the profound systemic implications of follicular failure. Recent evidence links aberrant circRNA expression patterns in ovarian tissues of POI patients to disruptions in granulosa cell fate decisions, skewing the balance between proliferation and apoptosis, and thus contributing to ovarian insufficiency.
One of the groundbreaking discoveries in POI research involves hsa_circ_0002021, an exosome-derived circRNA from umbilical cord mesenchymal stem cells, which functions as a ceRNA for miR-125a-5p. By modulating cyclin-dependent kinase 6 (CDK6) expression, circ_0002021 effectively counters granulosa cell senescence, restoring follicular function and offering a novel therapeutic avenue for POI. This highlights the potential for cell-free circRNA therapies that harness endogenous RNA networks to rejuvenate ovarian function. Moreover, the intersection of epigenetic regulation and circRNA function introduces another layer of complexity and therapeutic promise.
N⁶-methyladenosine (m⁶A) modification, a prevalent internal RNA methylation, has emerged as a critical epigenetic regulator influencing RNA stability, translation, and splicing. In POI, the m⁶A-mediated regulation of circRNAs such as circBRCA1 offers illuminating insights. CircBRCA1 levels are conspicuously reduced in POI patients, correlating with diminished ovarian reserves. Experimental models reveal that exosomes enriched with circBRCA1 ameliorate estrous cycle disruptions, decrease follicular atresia, and attenuate granulosa cell apoptosis and senescence. Mechanistically, the m⁶A demethylase FTO enhances circBRCA1 stability by removing methylation marks, enabling circBRCA1 to sponge miR-642a-5p and prevent its inhibitory interaction with the transcription factor FOXO1, a pivotal regulator of cell survival and oxidative stress responses. Such findings not only underscore the dynamic interplay between RNA modifications and circRNA functionality but also open innovative therapeutic windows targeting epitranscriptomic modifications.
The broader implications of m⁶A modification extend to fundamental aspects of folliculogenesis and oocyte maturation, processes intricately modulated by RNA methylation status influencing mRNA fate and the maternal-to-zygotic transition. Consequently, m⁶A represents a regulatory nexus that can modulate circRNA biogenesis, stability, and potential for translation—paradigms that are only beginning to be explored in the context of ovarian physiology and pathology. Targeted research dissecting the role of m⁶A-circRNA crosstalk in human follicular development could transform our understanding and management of ovarian disorders.
These groundbreaking insights into the molecular underpinnings of PCOS and POI place circRNAs at the forefront of reproductive medicine’s research frontier. The identification of specific circRNAs involved in disease mechanisms creates the prospect for highly sensitive diagnostic biomarkers that could detect early ovarian dysfunction before irreversible clinical consequences emerge. Furthermore, the possibility of manipulating circRNA expression or function presents tantalizing avenues for precision medicine, potentially overcoming the limitations of current hormone replacement therapies and conventional interventions.
The reviewed research synthesizes a growing body of literature supporting the centrality of circRNAs in ovarian disease, exemplified in comprehensive tables and illustrative models that depict their complex regulatory roles. Through ceRNA networks, interactions with miRNAs, participation in epigenetic modifications like m⁶A methylation, and involvement in signaling cascades, circRNAs orchestrate a multi-dimensional regulatory landscape governing folliculogenesis and ovarian health. Such multi-level regulation is essential to maintain reproductive homeostasis and prevent pathological states.
Moreover, exosome-derived circRNAs gain particular prominence as mediators of intercellular communication between ovarian somatic cells and the microenvironment. They represent a relatively untapped resource for non-invasive biomarker discovery and the development of RNA-based therapeutics. Targeting these molecules might not only restore ovarian function but also counteract the systemic metabolic disturbances emblematic of PCOS and the degenerative sequelae associated with POI.
In sum, the confluence of circRNA biology, epigenetic regulation, and ovarian physiology heralds a paradigm shift in how reproductive disorders are understood and managed. As molecular technologies, including high-throughput sequencing and epitranscriptomic profiling, continue evolving, they will enable deeper elucidation of circRNA networks and their functional outcomes. This will facilitate the development of precise and personalized therapeutic strategies, potentially revolutionizing care for millions of women affected by PCOS, POI, and related reproductive endocrine diseases globally.
Research in this domain remains nascent but poised for explosive growth, with future studies expected to unravel the full spectrum of circRNA functions in ovarian biology. Integrative approaches combining transcriptomics, proteomics, and epigenomics will be instrumental in developing robust circRNA-based diagnostic tools and targeted interventions, leading to improved reproductive health outcomes and enhanced quality of life for patients worldwide. Indeed, circRNAs offer a beacon of hope in the quest to understand and combat female reproductive disorders with lasting efficacy and specificity.
As this field advances, interdisciplinary collaborations spanning molecular biology, reproductive endocrinology, bioinformatics, and clinical medicine will be critical to translate these molecular discoveries into tangible health benefits. Promising early results underscore the importance of investing in circRNA research, not only to elucidate ovarian biology’s complexities but also to catalyze breakthroughs in the treatment of disorders that affect women’s health in profound and multifaceted ways.
Subject of Research:
Circular RNAs (circRNAs) and their regulatory roles in follicular development with implications for polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI).
Article Title:
Circular RNAs and mammalian follicular development: current insights and future prospects—an updated review.
Article References:
Li, H., He, T., Ma, D. et al. Circular RNAs and mammalian follicular development: current insights and future prospects—an updated review. Cell Death Discov. 11, 454 (2025). https://doi.org/10.1038/s41420-025-02661-z
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