During the reproductive cycle, key components of the Hippo signaling pathway are widely localized in ovarian cells, including oocytes, granulosa cells (GCs), theca cells and luteal cells, with dynamic expression patterns (27). For example, MST1 translocates to the nucleus from the cytoplasm gradually during oocyte development and achieves nuclear localization in the antral-stage oocytes (28). Similarly, YAP demonstrates stage-specific localization patterns in both oocytes and granulosa cells From primordial to preovulatory follicles, YAP progressively accumulates in the nucleus but relocates to the cytoplasm with markedly reduced expression in postovulatory luteal cells (28, 29). This observation is corroborated in a bovine ovary study, where microarray analysis revealed a significantly elevated YAP1 activation in larger developing follicles (5–10 mm) (30).

The Hippo signaling pathway governs the balance between primordial follicle dormancy and activation via mechanosensitive regulation. In mature ovaries, oocytes predominantly exist in a mechanically stressed state imposed by GCs and extracellular matrix (ECM), a condition critical for sustaining follicular dormancy and preserving female reproductive longevity (31). Subsequently, a series of studies confirms that mechanical signal during primordial follicle activation is involved in maintaining primordial follicle quiescence through activation of the Hippo signaling pathway (28, 32, 33). Furthermore, Liu et al. revealed that high cellular density promotes LATS1 SUMOylation at K830 residue (K829 in mice), enhancing kinase activity and amplifying Hippo signaling-mediated suppression of premature follicle activation (34–36).

Proliferation of GCs is also essential for primordial-to-primary follicle transition. Murine ovarian models demonstrate that activation of the Hippo signaling pathway downregulates pro-proliferative target genes CCN2 and CMYC, thereby inhibiting GCs proliferation while promoting apoptosis (27, 37–39). Recent work by Chen et al. further demonstrates that YAP transcriptional activity prevents GCs apoptosis through NEDD8-mediated K159 neddylation (40). Thus, the Hippo signaling pathway participates in folliculogenesis by regulating GCs proliferation/apoptosis. Notably, YAP also serves as a crucial hub for follicle-stimulating hormone (FSH)- and luteinizing hormone (LH)-mediated follicular development. Physiologically, FSH suppresses YAP-TEAD transcriptional activity in GCs, upregulating steroidogenic enzymes (CYP11A1, HSD3B2 and CYP19A1) to enhance estradiol synthesis and dominant follicle selection (41, 42). Conversely, in cumulus cells FSH induces YAP-TEAD interactions, upregulating cumulus expansion genes (EGFR, ADAM17, EREG, and PTGS2) to promote oocyte maturation (43). Additionally, Hippo-YAP signaling also modulates LH secretion and function. In adenohypophysis, YAP/TAZ is a negative regulatory factor for LH secretion (44). During LH-induced ovulation, transient inactivation of the Hippo signaling pathway promotes nuclear YAP1 binding to the amphiregulin (Areg) promoter, thereby activating ERK1/2 signaling to induce LH target gene expression. Subsequent LH-induced cAMP/PKA signaling sequesters YAP in the cytoplasm, driving GC luteinization (45–47). Collectively, mature follicle formation and ovulation depend on precisely coordinating the activity of the Hippo signaling pathway ( Supplementary Table 1 ).

Ovulatory dysfunction is a core diagnostic phenotype of PCOS, characterized by oligo-ovulation or anovulation, and its pathological mechanisms are closely associated with follicular developmental arrest and maturation impairment. Huang et al. observed that ovarian tissues of DHEA-induced PCOS murine models display an elevated YAP and phosphorylated YAP (p-YAP) expression but a significant reduction in p-YAP/YAP ratio (48). Mechanistically, this aberrant YAP1 activation in PCOS stimulates GCs hyperproliferation and downregulates luteinization-associated LH target genes (CYP11A1, STAR, LHCGR, PGR), which induces GC differentiation arrest, maintaining it in a non-luteinized state and triggering the pathological accumulation of immature ovarian follicles (49). Notably, impaired FSH signaling in PCOS synergistically contributes to dominant follicle selection failure (50). Recent studies reveal that YAP overexpression can impede follicular maturation by suppressing FSH responsiveness in GCs (42). In addition, a pathogenic androgen-YAP positive feedback loop may exist in PCOS. Jiang et al. found that androgens can attenuate YAP1 promoter methylation in a dose-dependent manner to increase YAP1 transcriptional activation in GCs (51). Concurrently, YAP-TEAD complex upregulation inhibits aromatase activity through suppressing CYP19A1 expression to affect the biotransformation of androgens to estrogens. This dual mechanism culminates in localized ovarian estrogen deficiency and androgen excess that obstruct follicle maturation and ovulation (42). Collectively, these findings suggest that abnormal YAP activation is intimately linked to ovulation dysfunction in PCOS ( Figure 2B ).

Observational clinical cohort studies have revealed that some PCOS patients exhibit DOR, but the exact mechanism is unclear (52). Dysregulation of ECM homeostasis in GCs may contribute to this pathology. For PCOS, ECM-related genes are down-regulated in the GCs, including ECM1, laminin α3/β1 (LAMA3/LAMB1) and fibronectin 1 (FN1), while matrix metalloproteinases (MMP-2, MMP-9) are upregulated, indicating a reduction in ECM stiffness (53–55). Furthermore, genomic analysis identified that the Ras homology growth-related (RHOG) gene, which regulates actin cytoskeleton polymerization, is abnormally elevated in PCOS patients’ GCs (56). When GCs perceive a decreased mechanical stress, F-actin is induced to form and hinders the Hippo signaling pathway, thereby triggering premature activation of dormant follicles (7, 27, 57). Pharmacological induction of actin polymerization corroborates this mechanism, as enhanced YAP nuclear translocation drives follicular recruitment (58). Thus, Hippo pathway dysregulation in GCs likely contributes to the pathological early follicular recruitment observed in PCOS-associated DOR ( Figure 2A ).

The ovarian microenvironment provides nutritional support and signaling transduction essential for normal follicular development (59). Patil et al. found that follicular growth arrest, luteal insufficiency and recurrent miscarriage in PCOS are associated with impairment of the vascular system (60). Moreover, follicular fluid in PCOS displays a down-regulation of pro-angiogenic genes (FGFR1, VEGFA, FN1), reflecting compromised vascular development (60). Genome-wide association analysis further identified a significant association between vascular endothelial growth factor (VEGF) gene polymorphisms and PCOS susceptibility (61). Mechanistic investigations demonstrate that neovascularization is dependent on a feed-forward loop between YAP/TAZ and VEGF-VEGFR2 signaling in endothelial cells mediated by cytoskeletal dynamics, while YAP suppression disrupts angiogenesis (62, 63). Consequently, diminished pro-angiogenic factors in PCOS microenvironments may impede vascular sprouting by inhibiting YAP signaling in endothelial cells.

Emerging evidence implicates there are relationships between the ovarian microenvironment exposure to environmental contaminants, such as perfluoroalkyl and poly-fluoroalkyl substances (PFAS), zearalenone (ZEN), microplastics and phthalates, and the risk of PCOS, which involve the Hippo signaling pathway dysregulation (64–68). Firstly, Perfluorooctanoic acid (PFOA) exposure can result in ovarian fibrosis and DOR, which are associated with abnormally high expression of YAP (69, 70). Secondly, co-exposure of polystyrene nanoparticles (PS-NPs) and phthalates induced PCOS-like phenotypes in mice via ROS-Hippo signaling activation (66, 71). Finally, single-cell RNA sequencing identifies the Hippo signaling pathway disruption as the molecular basis for ZEN-induced primordial follicle assembly defects (72). These findings establish a theoretical framework linking environmental toxicants to PCOS through the modulation of the Hippo signaling pathway, advancing etiological and therapeutic insights.

Overall, the Hippo signaling pathway plays a central role in ovarian dysfunction associated with PCOS. Under physiological conditions, this pathway is instrumental in the precise regulation of follicular development, granulosa cell proliferation and differentiation, hormonal response, and the ovulation process. In PCOS, however, significant dysregulation of this pathway (e.g., abnormal nuclear localization and sustained activation of YAP) triggers a cascade of pathological alterations, including imbalances in granulosa cell proliferation and differentiation, premature follicular activation and impaired angiogenesis, etc. Collectively, these disruptions contribute to ovulatory dysfunction, DOR and an aberrant ovarian microenvironment. The above findings not only provide deeper insights into the pathogenesis of PCOS-related ovarian dysfunction but also establish a rational basis for developing novel therapeutic strategies aimed at the Hippo signaling pathway.

The liver, a central organ in lipid homeostasis, exhibits Hippo-mediated dysregulation in PCOS (73). Clinical studies reveal a bidirectional association between PCOS and MASLD, though the underlying molecular mechanisms remain unclear (74, 75). Further exploration finds that hyperandrogenemia induces metabolic disruption in the liver of PCOS via increasing YAP expression and activity (73). Mechanistically, YAP is a co-activator of sterol regulatory element binding proteins (SREBP-1c and SREBP-2) and a nuclear cofactor for carbohydrate response element binding protein (ChREBP) that amplifies the expression of their target genes, thereby accelerating fatty acid and cholesterol production in hepatocytes (76, 77). In addition, inhibition of fatty acid oxidation mediated by the YAP-FXR axis can further exacerbate lipid deposition (78). In conclusion, the increased activity and expression levels of YAP in patients with PCOS are one of the major causes of their hepatic lipid metabolism disorders ( Figure 3 ).

Obesity is another important phenotype of lipid disorders in PCOS, affecting approximately 50% of these patients (79). Its pathological changes are characterized by adipose tissue excessive expansion (hypertrophy and/or hyperplasia) (80). Despite the lack of studies on the Hippo signaling pathway in adipose tissue of obese PCOS patients, researchers have observed significantly elevated YAP activity in white adipose tissue of humans and mice with obesity (81). Mechanistically, high YAP activity can exacerbate adipocyte hypertrophy by inducing Wnt5a-1 expression (82, 83). Therefore, high YAP activity in adipocytes of obese PCOS patients may contribute to their fat accumulation.

However, in normal-weight women with PCOS, adipogenic gene expression (PPARγ, CEBPα, AGPAT2) is abnormally elevated in their abdominal adipose-derived stem cells compared to healthy controls (84). Furthermore, a meta-analysis confirmed a significant association between PPARG gene polymorphisms and PCOS susceptibility (85). These imply that enhanced adipogenic tendency is a risk for non-obese patients. In recent years, a series of laboratory studies have demonstrated that the YAP-PPARγ regulatory axis is a key molecular mechanism for the differentiation of endocrine stem cells/pre-adipocytes to mature adipocytes (86–88). Therefore, there may be a lipogenic tendency mediated by the Hippo-YAP signaling pathway in preadipocytes of non-obese women with PCOS ( Figure 4 ).

IR as a core phenotype of metabolic disorders in PCOS, involves functional dysregulation across multiple organs (89). Hepatic lipid accumulation promotes IR by inducing the Hippo signaling pathway inactivation to amplify miR-27-mediated suppression of Akt signaling (73). Moreover, insulin sensitivity and glucose homeostasis in adipose tissue are negatively correlated with YAP activity (90, 91). Skeletal muscle, as another major target organ for insulin, occurs IR is closely related to reduced YAP levels (92, 93). Mechanistically, inhibited YAP can lead to IR by inducing mitochondrial fatty acid oxidizing capacity dysfunction in skeletal muscle (93). Furthermore, although not clear in skeletal muscle, reduced YAP/TAZ activity has been shown to cause downregulation of IRS1 phosphorylation levels in endometrial cancer cells, which in turn affects insulin sensitivity (94). Notably, hepatic lipid accumulation, adipose tissue dysfunction, mitochondrial dysfunction and IRS1/PI3K/Akt signaling inhibition in skeletal muscle underlies IR pathogenesis in PCOS (91, 95, 96). Collectively, Hippo-YAP dysregulation underpins IR pathogenesis through hepatic steatosis, adipocyte dysfunction, and skeletal muscle metabolic inflexibility.

Hyperinsulinemia (HI), caused by pancreatic β-cell hypersecretion, exhibits a bidirectional pathological association with IR (89). Emerging clinical evidence suggests HI may precede IR onset in PCOS, correlating with hyperandrogenemia (97, 98). Prenatal androgen exposure induces β-cell apoptosis, whereas postnatal exposure triggers compensatory β-cell hyperplasia and HI (99–101). Mechanistic studies demonstrate that the Hippo pathway collaborates with neurogenin 3 (NGN3) to silence YAP during endocrine lineage specification, which is a prerequisite for functional β-cell differentiation (102–104). Conversely, aberrant YAP activation disrupts its functional maturation (105). Intriguingly, the upregulation of YAP expression in mature β-cells stimulates proliferation without affecting function (106–108). Given androgen-induced YAP activation in hepatic and ovarian tissues, we propose that hyperandrogenemia drives HI via ectopic YAP activation in pancreatic β-cells, establishing a self-reinforcing endocrine-metabolic loop.

In summary, dysregulation of the Hippo signaling pathway appears to be a critical node in the molecular mechanisms underlying metabolic disturbances in PCOS. This pathway not only contributes to hepatic lipid accumulation by regulating lipid synthesis and lipolysis, but also mediates adipose tissue dysfunction. Furthermore, it extensively influences insulin signaling transduction in peripheral tissues, promoting the development of systemic insulin resistance and hyperinsulinemia. These mechanisms highlight the significant role of the Hippo signaling pathway in the systemic metabolic dysregulation of PCOS, providing new perspectives on the disorder’s molecular underpinnings.

Follicular development modulation represents a cornerstone for addressing PCOS-related infertility. Laparoscopic ovarian drilling (LOD), as a surgical intervention for clomiphene citrate (CC)-resistant patients, inhibits Hippo signaling to promote primordial follicle activation, though its efficacy remains debated (7, 120–123). Emerging evidence suggests that the Hippo signaling pathway activation represents an effective therapeutic mechanism in PCOS patients with impaired follicular development. Huang et al. observe that verteporfin (a YAP-TEAD interaction inhibitor) treatment in PCOS mice can reduce serum anti-Müllerian hormone (AMH) levels and restore follicular growth (48). Furthermore, YAP also serves as a molecular hub of biopharmaceutical and nutraceutical interventions for PCOS. Firstly, anti-growth factor-releasing peptide antibodies alleviate PCOS phenotypes in murine models, such as weight gain, estrous cycle disruption, ovarian morphologic aberrations and hormonal imbalances, via silencing Gαq/11 or YAP in GCs (124). Secondly, adding n-3 polyunsaturated fatty acids (PUFAs) to the diet significantly alleviated hormonal and estrous cycle disturbances in PCOS mice by reducing YAP1/Nrf2 signaling in GCs (125). Therefore, targeting the Hippo-YAP signaling pathway is a promising therapeutic strategy for restoring fertility in PCOS patients.

Weight management constitutes the cornerstone of metabolic intervention in PCOS, particularly in patients with comorbid overweight/obesity (79). Current therapies reduce adipocyte hypertrophy but fail to modulate hyperplasia (80, 126). A mechanistic study by Wang et al. has revealed that YAP inhibition selectively induces apoptosis in mature adipocytes (81). Notably, the adipogenic marker PPARγ in preadipocytes exhibits a significant correlation with PCOS metabolic parameters, which is negatively regulated by YAP and TEAD4 (127–129). In addition, MST1/2 gene deletion enhances adipocyte mitochondrial autophagy activity through a non-YAP-dependent pathway, thereby elevating the efficiency of energy metabolism and inhibiting dietary obesity (130). Liraglutide as a common insulin sensitizer in PCOS patients, despite its known glucose-lowering effect, also inhibits the proliferation of preadipocytes through activation of the Hippo signaling pathway but also accelerates adipogenic differentiation (131).

IR management is the center of PCOS metabolic intervention. Experimental evidence indicates that adipocyte-specific YAP/TAZ knockout significantly enhances insulin sensitivity in obese murine models (90, 132). In addition, both clinical observations and animal studies demonstrate reduced proportions of insulin-sensitive type I muscle fibers in PCOS, which may be an important pathological basis for skeletal muscle IR (96, 133). Remarkably, LATS1/2 knockout in mice can significantly increase the percentage of type I muscle fibers in skeletal muscle (134). Thus, precise modulation targeting the Hippo signaling pathway may provide an innovative therapeutic strategy to ameliorate PCOS metabolic disorders.

Although current clinical guidelines for PCOS have not yet incorporated systemic anti-inflammatory treatment regimens, accumulating experimental evidence underscores the pivotal role of inflammatory modulation in improving reproductive and metabolic outcomes in PCOS (109, 126). Recently, Wang et al. proposed a potential molecular pathway of PUFAs in PCOS treatment. Their findings demonstrate that PUFAs significantly upregulate anti-inflammatory gene expression and induce macrophage M2-like polarization by inhibiting RhoA-YAP1 signaling (135, 136). This implies a potential therapeutic value of the Hippo-YAP signaling pathway remodeling immunocyte phenotype for anti-inflammatory interventions in PCOS.

PCOS combined with MASLD significantly constrains therapeutic options, exacerbates disease management complexity and amplifies long-term adverse outcomes (137). Researchers have found that hyperlipidemia and IR are shared pathological foundations between PCOS and MASLD, suggesting potential synergistic therapeutic targets (138). In clinical practice, glucagon-like peptide-1 (GLP-1) receptor agonists, thiazolidinediones, and statins have demonstrated dual therapeutic effects, their side-effect profiles necessitate novel approaches (139). Animal experiments have confirmed that YAP knockout in MASLD model mice can effectively reduce hepatic triglyceride (TG) and Perilipin 2 (PLIN2) levels and ameliorate lipid metabolism disorders (140). Moreover, emerging therapeutic approaches utilizing chrysanthemum lactone (PAR), anti-miR-199a-5p exosome and Hep@PGEA/MST1 nanocarrier demonstrate reducing hepatic lipid burden effects by disrupting the Hippo signaling pathway (141–143). These findings collectively propose that targeting the expression of Hippo signaling components to regulate metabolic disorders in the liver may be a novel way to treat PCOS-MASLD comorbidities.

Notably, LATS1 activity in GCs is negatively correlated with steroidogenic acute regulatory protein (StAR)-mediated estrogen synthesis (144). However, pathological estrogen elevation significantly increases the risk of ovarian hyperstimulation syndrome (OHSS), a serious complication frequently observed in PCOS patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments (145). Consequently, activation of LATS1 in GCs may be a preventive strategy against OHSS during PCOS patients’ assisted reproductive therapy.

In conclusion, targeting the Hippo-YAP signaling pathway represents a promising multifaceted therapeutic strategy for PCOS, encompassing key areas such as reproductive function, metabolic regulation, inflammatory response and comorbidity management. Specifically, modulation of this pathway could potentially promote follicular development, improve metabolic disorders, regulate immune responses and prevent complications such as OHSS and MASLD.

The current clinical management of PCOS is still based on symptomatic relief as the main goal with limited therapeutic options (146). To address this current situation, developing stage-specific and tissue-targeted Hippo pathway modulation strategies holds significant clinical promise. However, the clinical translation of such strategies faces several challenges, including limitations in targeting precision, delivery efficiency, biocompatibility, safety, stability, and scalable production. Therefore, future research should emphasize multidisciplinary collaboration to optimize delivery systems, thereby providing more robust and precise tools for disease treatment. Furthermore, significantly upregulated YAP expression has been observed in ovarian granulosa cells of PCOS patients, suggesting that quantitative assessment of Hippo signaling biomarkers (e.g., p-YAP and YAP levels) may facilitate early diagnosis and real-time therapeutic monitoring (51).