Polycystic ovary syndrome (PCOS), alternatively referred to as Stein-Leventhal syndrome, constitutes one of the most prevalent reproductive, endocrine, and metabolic disorders affecting women of reproductive age (1). This condition is potentially associated with both genetic and environmental determinants. PCOS is principally characterized by hyperandrogenemia (HA), insulin resistance (IR), ovulatory dysfunction, and polycystic alterations in the ovaries (2). The estimated global prevalence of PCOS ranges from approximately 5% to 15% (3).

Autophagy is a cellular self-digestion process that serves as a critical mechanism for maintaining intracellular homeostasis by degrading and recycling intracellular components (4). In response to various stress conditions, such as nutrient deprivation, oxidative stress, or mechanical stress, cells detect these stress signals, leading to the inhibition of mTOR and/or activation of AMPK and other core pathways, thereby initiating autophagy to ensure normal cellular survival and function (5). Autophagy plays a pivotal role in cellular immunity, affecting the development, differentiation, function, and homeostasis of immune cells, including T cells, B cells, and macrophages (6). Moreover, autophagy modulates inflammatory responses by influencing the production of pro-inflammatory cytokines, such as IL-1β and TNF-α, while cytokines like TNF-α, IL-1, IL-2, IL-6, and TGF-β can also induce autophagy (7). The interaction between autophagy and pro-inflammatory factors suggests a mechanism for balancing pro- and anti-inflammatory responses. This balance helps prevent excessive cellular and tissue damage.

Autophagy is integral to maintaining normal physiological functions. Disruption of autophagy can impair the immune functions of healthy organs and tissues, potentially leading to various diseases, including infections, autoimmune disorders, cancer, and metabolic disorders. In the context of metabolic disorders, dysregulated autophagy can exacerbate their progression, manifesting in conditions such as insulin resistance, diabetes, obesity, atherosclerosis, and osteoporosis. Furthermore, autophagy dysfunction is implicated in the pathophysiology of PCOS, where aberrant autophagy may constitute a critical pathway linking the dysfunction of multiple organ systems, thereby contributing to the onset and progression of the syndrome.

Emerging evidence underscores that the reproductive and metabolic dysfunctions in PCOS are not isolated to a single organ but arise from intricate crosstalk among key metabolic and endocrine tissues. The “liver-adipose-ovary circuit” refers to the pathophysiological network formed during the pathogenesis of PCOS, where the liver, adipose tissue, and ovaries interact and exacerbate each other through mechanisms such as autophagy dysfunction, chronic low-grade inflammation, and metabolic disorders (such as insulin resistance and hyperandrogenism). This circuit describes a self-perpetuating, vicious cycle wherein dysfunction in one organ exacerbates abnormalities in the others, collectively driving and amplifying the core features of PCOS through shared mechanisms centered on autophagy dysregulation, chronic low-grade inflammation, and metabolic derangement.

Mammals possess three primary types of adipocytes—white, beige, and brown, which are organized into distinct depots throughout the body (9). White adipose tissue (WAT) serves as a reservoir for fat storage during periods of energy surplus and facilitates the mobilization and release of fat during energy deficits. In animals, the two predominant forms of WAT are subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (10). Brown adipose tissue (BAT) is integral to weight regulation and metabolic control, as its activation enhances energy expenditure, mitigates obesity, reduces blood glucose and lipid levels, and secretes factors that influence both local and systemic energy metabolism. White adipocytes exhibit significant plasticity, enabling their trans-differentiation into beige adipocytes, which share numerous morphological and functional characteristics with brown adipocytes, particularly under stimuli such as exercise, cold exposure, and other factors (11).

Autophagy is essential for maintaining WAT homeostasis, primarily through three mechanisms: (1) Lipid regulation involves the modulation of fatty acid release through the autophagy-mediated degradation of lipid droplets (12). (2) Adipocyte differentiation is influenced by autophagy, which facilitates the transformation of preadipocytes into mature adipocytes. The deletion of autophagy-related genes, such as Atg7, has been shown to inhibit adipogenesis (13, 14). (3) In terms of stress adaptation, autophagy plays a crucial role in maintaining WAT homeostasis during nutritional fluctuations induced by endogenous or environmental stimuli. This is achieved by recycling damaged organelles, thereby underscoring autophagy’s dynamic homeostatic regulatory properties (15). Furthermore, autophagy positively impacts BAT by preserving mitochondrial quality and thermogenesis, while also promoting the differentiation of brown adipocytes (16). Impairments in autophagy can result in BAT dysfunction, where defective mitophagy leads to the accumulation of reactive oxygen species (ROS), activation of inflammatory pathways, and subsequent inflammatory responses (17).

The liver, as the body’s metabolic hub, is integral to processes such as nutrient synthesis and breakdown, hormone inactivation, and biotransformation (36). Within these processes, hepatic autophagy is vital for maintaining metabolic homeostasis. Autophagy serves as a protective mechanism by efficiently removing damaged organelles and proteins, thereby safeguarding hepatocytes from further damage (37). Conversely, aberrant autophagy responses can induce hepatocyte death and liver dysfunction, a phenomenon observed in various hepatic pathologies, including viral hepatitis, NAFLD, liver fibrosis, and hepatocellular carcinoma (38). Additionally, the liver plays a significant role in immune modulation (39). Hepatic autophagy is intricately connected to the activity of immune cells within the liver, such as Kupffer cells and T cells.

NAFLD is a chronic hepatic disorder characterized by the accumulation of fat in the liver and is frequently associated with metabolic conditions such as obesity, insulin resistance, and type 2 diabetes (40). The prevalence of NAFLD is notably higher among women with PCOS, and conversely, women with NAFLD are more likely to exhibit PCOS. This reciprocal relationship suggests a strong interconnection between the two conditions, potentially establishing a bidirectional vicious cycle (41).

The impaired autophagy suppression in NAFLD patients contributes to lipid accumulation, the release of pro-inflammatory factors, and the generation of reactive oxygen species, which collectively can lead to excessive activation of the JNK pathway in hepatocytes, culminating in hepatic insulin resistance (42). The resultant state of hyperinsulinemia associated with hepatic insulin resistance can further enhance Akt/mTOR signaling, inhibit autophagy, and facilitate the progression of hepatic steatosis (43, 44).

Moreover, research indicates that hepatic insulin resistance downregulates the activity of the sex hormone-binding globulin (SHBG) gene promoter, thereby inhibiting SHBG gene transcription and reducing hepatic SHBG production. Since SHBG serves as the primary binding protein for androgens, decreased levels result in increased circulating free androgens, ultimately leading to hyperandrogenemia (45). Elevated circulating androgens form activated androgen receptor-ligand complexes that translocate to the nucleus, where they bind to androgen response elements (AREs) within the SHBG promoter region and recruit co-repressors to inhibit SHBG gene transcription. This mechanism allows androgens to directly downregulate SHBG gene expression, thereby reducing SHBG mRNA production and further inhibiting hepatic SHBG synthesis (46–48). Consequently, androgen levels continue to rise, establishing a vicious positive feedback loop that exacerbates androgen-related symptoms in patients with PCOS. Furthermore, elevated circulating free androgen levels disrupt the negative feedback regulation of the hypothalamic-pituitary-ovarian (HPO) axis (Figure 1). This condition diminishes the feedback inhibition of luteinizing hormone (LH), resulting in disrupted gonadotropin-releasing hormone (GnRH) pulsatility and excessive LH release, which further exacerbates abnormal androgen levels (34).

These findings suggest that abnormal liver autophagy may impair ovarian function via insulin resistance and hyperandrogenemia, contributing to ovarian metabolic disorders and potentially playing a role in PCOS pathophysiology.

Kupffer cells, the resident macrophages of the liver, play a crucial role in the hepatic immune response. Insulin resistance leads to excessive activation of the mTOR pathway in hepatocytes, inhibiting autophagy (43, 44). Impaired autophagy hinders clearance of damaged mitochondria and lipid droplets (49), causing lipid accumulation. This induces lipotoxicity, activating Kupffer cells via TLR4 to produce ROS and secrete TNF-α and other pro-inflammatory cytokines, promoting polarization toward the M1 phenotype and resulting in liver injury and fibrosis (50). ROS and mtDNA release from damaged mitochondria activate the NLRP3 inflammasome, increasing secretion of IL-1β and IL-18 and exacerbating inflammation (51). Deletion of Atg5 in Kupffer cells of high-fat diet mice induces M1 polarization and inflammatory mediator secretion (52). These factors can disseminate systemically, triggering systemic inflammation (53).

PCOS prevalence is linked to inflammatory factors that infiltrate ovarian tissue, disrupting follicular development and ovulation (54). Dysregulated hepatic autophagy disrupts the M1/M2 macrophage balance, releasing inflammatory mediators that impair ovarian physiology, associated with PCOS pathophysiology. Chronic inflammation worsens insulin resistance and hyperandrogenemia, creating a vicious cycle.

Impaired hepatic autophagy correlates with pro-inflammatory T cells. Th1 cells secrete IL-2 and IFN-γ to enhance cellular immunity, while Th2 cells secrete IL-4 for humoral immunity (55). In high-fat diet mice, reduced Th2 and increased CD8+ T, Th1, and B cells link to NAFLD with fibrosis, involving impaired autophagy, ER stress, and NLRP3 activation (56). PCOS patients show a Th1-dominant response, with elevated Th1/Th2 ratio correlating with higher BMI, indicating chronic low-grade inflammation (57). Th1 dominance may exacerbate insulin resistance and hyperandrogenism. The shared Th1/Th2 shift in NAFLD and PCOS suggests autophagy deficiencies and T-cell dysfunction contribute to their common pathophysiology.

In the context of PCOS, this intricately regulated network experiences multidimensional dysregulation. During the typical development of ovarian follicles in mammals, the autophagic activity within follicular cells is vital for preserving oocyte quality, and any disruption in this process may result in female infertility (61).

On the one hand, autophagy plays a significant role in the regulation of follicular atresia. A process wherein the number of follicles within the ovaries diminishes with age, with the majority undergoing natural atresia at various developmental stages. This process is modulated by both apoptosis and autophagy. Research findings suggest that electron microscopy has identified a significant presence of lysosomes and autophagosomes within the cytoplasmic matrix of rat oocytes, indicating that active autophagy may play a role in oocyte development and maturation. Hormonal regulation also appears to influence autophagic processes. For example, under conditions of oxidative stress, melatonin facilitates the survival of granulosa cells (GCs) by inhibiting autophagy during follicular atresia, achieved through the suppression of the transcription factor forkhead box O1 (FOXO1) (62). Treatment with follicle-stimulating hormone (FSH) has been shown to suppress autophagy in GCs (63), suggesting that FSH may protect mouse granulosa cells from oxidative damage by inhibiting mitophagy (64). Furthermore, FSH inhibits apoptosis in GCs via the PI3K/Akt/mTOR signaling pathway and FOX gene transduction in human ovarian GCs, which is essential for maintaining follicular atresia and promoting GCs proliferation (65).

On the other hand, autophagy exerts an influence on ovarian reserve, thereby affecting follicular and oocyte development. In instances of follicular depletion, the anti-Müllerian hormone (AMH), synthesized by GCs of early-stage developing follicles, can safeguard the immature follicle reserve by inhibiting autophagy within the ovary through the suppression of FOXO3/FOXO3A phosphorylation, which otherwise leads to the activation of immature follicles (66). The Atg7 gene, a pivotal autophagy-related gene essential for autophagosome formation, maintains stable expression levels throughout all stages of oogenesis. Mice deficient in the Atg7 gene typically exhibit reduced litter sizes and experience a gradual decline in fertility. These mice display a significant reduction in the number of germ cells and primordial follicles, with numerous follicles demonstrating structural abnormalities or functional loss. This evidence suggests that autophagy is crucial for germ cell survival (67). Furthermore, studies have indicated that oxidized low-density lipoprotein (OxLDL) may exacerbate fertility challenges in obese women by inducing autophagic cell death in ovarian granulosa cells. These research findings reveal that the autophagy process within follicles and their overall metabolic status significantly influence follicular development, with these effects carrying profound implications for reproductive health.

Macrophages, dendritic cells (DCs), neutrophils, eosinophils, mast cells, B cells, T cells, and natural killer (NK) cells constitute the immune cell population present in the ovaries (68). These ovarian immune cells perform a variety of functions, including phagocytosis and antigen presentation, tissue remodeling through proteolytic enzyme activity, and the secretion of soluble mediators such as cytokines, chemokines, and growth factors (69). Among these, macrophages are the most prevalent immune cells within ovarian tissue and are integral to maintaining the stability of the ovarian microenvironment (70). In patients with PCOS and corresponding animal models, there is an observed increase in the number of M1 macrophages in both peripheral blood and ovarian tissue, accompanied by an elevated M1/M2 macrophage ratio and increased levels of C-reactive protein and proinflammatory factors (71). Studies have demonstrated that in the context of PCOS, macrophage-derived proinflammatory factors, such as IL-6, IL-18, and TNF-α, contribute to dysregulated autophagy in granulosa cells. Patients with PCOS exhibit upregulated expression of autophagy-related genes ATG5 and ATG7 in granulosa cells, along with an increased LC3II/LC3I ratio. This dysregulation may impair the processes of follicular growth, maturation, and atresia, thereby leading to disorders in follicular development and adversely affecting female fertility (59, 60).

Ovarian ovulation is characterized by localized damage to the follicle wall, followed by a healing process that constitutes an acute aseptic inflammatory response. Within the ovary, DCs represent the primary population of bone marrow-derived immune cells surrounding mature oocytes. As pivotal immune regulators, DCs facilitate follicle rupture and oocyte release by detecting inflammatory signals and modulating cytokine release. Autophagy plays a dual regulatory role in this process: it inhibits the immunogenic maturation of DCs, for instance, by decreasing MHC-II expression, while simultaneously promoting their tolerogenic maturation, such as through the induction of Treg differentiation (72). Studies have identified that abnormalities in DC maturation and cytokine production may contribute to atypical oocyte development in patients with PCOS (73). In the context of PCOS, hyperandrogenemia and insulin resistance may disrupt the autophagic equilibrium in DCs, resulting in impaired immune tolerance and the aberrant release of pro-inflammatory cytokines, including IL-1β and TNF-α. This disruption subsequently fosters chronic ovarian inflammation and ovulatory dysfunction.

In ovarian tissue affected by PCOS, insulin resistance and hyperandrogenemia have been identified as factors associated with low-grade inflammation. Recent studies have illustrated that abnormal inflammatory processes can disrupt normal ovarian follicular dynamics, resulting in compromised oocyte quality, anovulation, and subsequent infertility (74). High Mobility Group Box 1 (HMGB1), a critical inflammatory mediator, is found at significantly elevated levels in both the blood circulation and follicular fluid of women with PCOS, in conjunction with insulin resistance (75, 76). HMGB1 exacerbates inflammation and insulin resistance via the NF-κB signaling pathway and directly induces autophagy in ovarian granulosa cells. This is evidenced by increased LC3B-II/I ratios and ATG7 levels, along with decreased SQSTM1 levels. Such excessive autophagy leads to a reduction in granulosa cell numbers and disrupts insulin signaling pathways, including AKT phosphorylation, GLUT4 translocation, and glucose uptake, thereby impairing ovarian function. Research has demonstrated that these pathological effects can be reversed by inhibiting HMGB1-mediated autophagy (77).

Insulin-like growth factor-1 (IGF-1) is a hormone implicated in the induction of inflammatory cytokine production. Elevated IGF-1 levels have been documented in PCOS and may be associated with autophagy (78). Recent research involving zebrafish ovaries suggests that locally synthesized IGF-1 within the ovaries facilitates the growth and development of primary follicles (79). IGF-1 has been shown to regulate cellular autophagy via the PI3K/mTOR signaling pathway (80). Targeting IGF-1 to modulate the initiation of autophagy through the mTOR pathway may enhance therapeutic outcomes for patients with PCOS and early-stage endometrial cancer (81).