Causes and treatments of polycystic ovary syndrome linked to obesity

Autophagy is a cellular process essential for maintaining homeostasis by degrading damaged organelles and proteins via lysosomes. It encompasses three primary types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy is particularly important in the ovary, where it plays a pivotal role in regulating oocyte development, follicular growth, and atresia. In PCOS, especially in the context of obesity, dysregulated autophagy disrupts GCs and TCs function, contributing to follicular arrest and anovulation [21]. Notably, this dysregulation is cell-type specific: excessive autophagy is often observed in GCs, while autophagic impairment is more common in TCs [22 –27].

IR is tightly linked to altered autophagy in PCOS, particularly in GCs. In PCOS patients, reduced ATG7 levels correlate negatively with HOMA-IR, indicating disrupted autophagy [28]. IR promotes mitochondrial dysfunction and oxidative stress, activating mitophagy via the mitochondrial unfolded protein response (UPR^mt). This leads to GC dysfunction and premature ovarian aging [29]. Conversely, excessive autophagy activation—especially via high mobility group box 1 (HMGB1)—negatively regulates insulin signaling by suppressing IRS-1 and inhibiting the PI3K/AKT pathway, creating a self-perpetuating loop between IR and imbalance between autophagic activation and degradation [30, 31]. This bidirectional interaction is a critical driver of metabolic and reproductive dysfunction in obese PCOS.

HA also induces excessive autophagy in GCs via multiple converging molecular mechanisms. It suppresses the PI3K/AKT/mTOR axis and promotes ROS accumulation—two key pathways known to trigger autophagic activation [32 –34]. These changes are consistently observed in clinical and animal models, evidenced by elevated LC3-II/LC3-I ratios and reduced p62 expression [23 –25]. Additionally. BORC complex subunit BOP1 (BOP1) overexpression triggers a nucleolar stress response, further inhibiting mTOR signaling via p53, thereby exacerbating autophagic activity [23]. In parallel, CISD2 upregulation suppresses mitophagy, leading to ROS buildup and mitochondrial dysfunction, which disrupts GC survival [35]. Wnt5a has emerged as a potential modulator capable of restoring autophagic homeostasis in HA-induced PCOS. By downregulating PI3K/AKT/mTOR signaling, Wnt5a attenuates excessive autophagy and alleviates GC dysfunction in experimental models [36]. Although most evidence centers on GCs, HA disrupts autophagy in peripheral metabolic tissues. In skeletal muscle cells, HA impairs glucose uptake by inhibiting the mTORC1-autophagy axis, resulting in impaired glucose uptake and aggravated IR [37]. Additionally, the mitophagy-related gene MAP1LC3A is positively correlated with serum testosterone in PCOS patients and may serve as a biomarker of ovulatory dysfunction [38]. These findings underscore the role of HA in disrupting both canonical autophagy and mitophagy across multiple tissues, thereby promoting both ovarian and metabolic dysfunction in obese PCOS.

FFAs in obesity-related PCOS disrupt autophagy homeostasis in both TCs and GCs, worsening follicular and metabolic dysfunction. In TCs, FFAs impair autophagosome–lysosome fusion, leading to p62 accumulation. This suppression is associated with upregulated CYP17A1 and PAI-1 expression, which enhance androgen production via ROS/p38 and JNK signaling [22]. In GCs, FFAs stimulate the secretion of adipokine chemerin, which excessively activates autophagy in GCs by inhibiting the PI3K/Akt/mTOR pathway [39 –41]. The resulting excessive autophagy activation leads to mitochondrial damage and cellular stress, thereby impairing folliculogenesis. This pathophysiological axis links lipid metabolism, autophagy dysregulation, and ovarian dysfunction. Together, FFAs induce divergent autophagic phenotypes—suppressed flux in TCs and excessive activation in GCs—via distinct molecular pathways. These effects collectively disrupt follicular integrity and contribute to reproductive and metabolic abnormalities of obese PCOS.

In patients with PCOS and obesity, autophagy is primarily marked by excessive activation of ovarian GCs and impaired autophagy in TCs. This dysregulation is driven by several factors, including IR, HA, and abnormal lipid metabolism. These factors contribute to abnormalities in follicular development and a cycle of metabolic dysfunction. Future research should aim to dissect cell-specific autophagic pathways and develop targeted interventions to restore autophagic balance and improve reproductive-metabolic outcomes in PCOS.

Chronic low-grade inflammation (CLGI), characterized by the persistent elevation of pro-inflammatory mediators such as CRP, IL-6, and TNF-α, is a defining feature of obesity-associated PCOS [42 –47]. Compared with non-obese patients with PCOS, those with obesity demonstrated more severe inflammatory responses, including increased levels of IL-6, TNF-α, neutrophil-to-lymphocyte ratio (NLR), high-sensitivity C-reactive protein (hs-CRP), and mean platelet volume (MPV) levels [48, 49]. These systemic alterations reflect a sustained inflammatory milieu driven by both metabolic stress and endocrine perturbations.

At the molecular level, CLGI in PCOS is orchestrated by aberrant immune cell activation, inflammasome signaling, and tissue-specific inflammatory responses. In the liver, overnutrition suppresses AMP-activated protein kinase (AMPK) activation, leading to activation of the NLRP3 inflammasome and IL-1β maturation—key events in initiating hepatic inflammation. Simultaneously, IRS1 Ser307 phosphorylation further links metabolic stress to immune dysregulation [50]. In the endometrium, the reduced abundance of CD56⁺ NK cells and CD163⁺ M2 macrophages compromises local immune tolerance, favoring a pro-inflammatory microenvironment [51, 52]. In ovarian GCs, inflammatory stimuli such as advanced glycation end-products (AGEs) and high glucose activate the p38 MAPK pathway, enhancing secretion of IL-6 and TNF-α and impairing follicular development [53].

In addition to canonical immune pathways, endocrine-immune crosstalk reinforces the inflammatory state. While IR and HA are known to contribute to inflammation, emerging evidence suggests that inflammation may independently drive metabolic and reproductive dysfunction in PCOS. For example, elevated IL-15 levels in patients and animal models activate p38 and JNK signaling in GCs, stimulating pro-inflammatory cytokine production and exacerbating steroidogenic imbalance [54]. Furthermore, adipokines such as chemerin accumulate in the follicular fluid and directly impair oocyte competence by disrupting intracellular signaling [40, 41, 55].

Dysregulated lipid metabolism further exacerbates CLGI by altering adipose tissue homeostasis and immune balance. PCOS patients frequently exhibit dyslipidemia, typified by elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels alongside reduced high-density lipoprotein cholesterol (HDL-C). These lipid abnormalities positively correlate with inflammatory markers such as CRP and the systemic immune-inflammation index (SII) [56, 57]. Increased leukocyte counts and immune cell activation further reflect this link [58]. Notably, compensatory mechanisms may exist. In PCOS mouse models, the peptide hormone adropin promotes M2 macrophage polarization and eNOS/PPARγ-mediated browning of white adipose tissue, thereby mitigating inflammation and restoring metabolic homeostasis [59].

Obesity may exacerbate CLGI in PCOS through the promotion of HA, IR, and lipid metabolism disorders, which in turn aggravate metabolic dysfunction. However, inflammation may also function as an independent pathogenic factor in PCOS, potentially contributing to disease heterogeneity between obese and non-obese patients. Future research should focus on clarifying causal relationships and developing therapeutic strategies targeting the metabolism-inflammation axis.

Endoplasmic reticulum stress (ERS) is a cellular adaptive response triggered by disruptions in ER homeostasis, affecting protein folding, calcium balance, and lipid processing. Moderate levels of ERS are essential for oocyte maturation [60]. However, excessive or sustained ERS has been demonstrated to significantly exacerbate the pathological progression of PCOS [61].

Clinical and experimental studies have consistently demonstrated heightened ERS in PCOS, particularly in ovarian GCs. Elevated levels of ERS markers, such as glucose-regulated protein 78 (GRP78) and activating transcription factor 4 (ATF4), have been identified in the GCs of PCOS patients [62, 63]. Animal models further corroborate these findings, showing the activation of key ERS pathways, including inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), correlating with increased GC apoptosis and impaired follicular development [61, 64].

A primary upstream trigger of ERS in PCOS is metabolic overload, particularly FFA accumulation associated with obesity. Elevated FFAs activate PERK and IRE1α signaling in GCs, inducing apoptosis and steroidogenic dysfunction. Simultaneously, FFAs upregulate CYP17A1 and PAI-1 via the ROS/p38 and JNK axes, enhancing androgen synthesis and amplifying ERS. Inflammatory cytokines released from adipose tissue, such as IL-6 and TNF-α, further intensify ER stress signaling, indicating cross-talk between metabolic and immune perturbations [61 –63, 65, 66].

Hyperglycemia and glucose toxicity, frequently observed in insulin-resistant PCOS patients, represent an additional ERS trigger. Persistent high glucose conditions exacerbate oxidative damage and upregulate ERS markers such as ATF4 and XBP1 in GCs, promoting apoptosis and compromising follicular integrity [65, 67]. This hyperglycemia-induced ERS further disrupts systemic insulin sensitivity, creating a detrimental feedforward loop that aggravates metabolic dysfunction.

HA exacerbates ERS through oxidative and inflammatory mechanisms. Androgen excess activates the NOX4/ROS axis, leading to sustained PERK–ATF4 signaling and induction of the LINC00173–HRK apoptotic pathway, while concurrently inhibiting PI3K/Akt-mediated survival signaling [64, 68]. In parallel, HA enhances the IRE1α-TXNIP-NLRP3 inflammasome activation, leading to pyroptosis and local inflammation in GCs [69, 70]. Additionally, HA promotes lipid peroxidation and ferroptosis in GCs, while systemically inducing ERS in uterine smooth muscle, impairing contractility and implantation, and in pancreatic β-cells, driving hyperinsulinemia [71 –74].

In conclusion, ERS in PCOS represents a critical downstream effector of integrated metabolic and endocrine insults. By disrupting GC survival, steroidogenesis, and tissue homeostasis, sustained ERS contributes to follicular arrest, chronic inflammation, and systemic dysfunction. Therapeutic strategies targeting ERS-related pathways may offer novel avenues for restoring reproductive and metabolic balance in PCOS.

Gut microbiota plays a central role in host metabolic homeostasis, immune regulation, and endocrine signaling. Through fermentation of dietary fibers, it produces short-chain fatty acids (SCFAs), maintains intestinal barrier integrity, and regulates tryptophan and bile acid metabolism. These microbial metabolites serve as signaling molecules that regulate systemic inflammation, glucose metabolism, and hormonal balance.

In obese PCOS patients, gut dysbiosis is a common feature, marked by reduced α-diversity, depletion of beneficial microbes (e.g., Bacteroidetes, Firmicutes), and increased abundance of pro-inflammatory taxa (Proteobacteria, Fusobacterium, Prevotella) [75, 76]. The decline in butyrate-producing bacteria and reduced SCFA levels, weakening the intestinal barrier and facilitating lipopolysaccharide (LPS) leakage into the circulation. LPS activates the TLR4/NF-κB pathway, inducing CLGI. Moreover, SCFAs deficiency promotes epitranscriptomic changes, such as m6A methylation of FOSL2, which activates the NLRP3 inflammasome and enhances IL-1β secretion [49].

In parallel, the altered microbial composition impairs lipid and bile acid metabolism. Enrichment of Megamonas and Dialister further contributes to IR via disruptions in fatty acid and sphingolipid signaling pathways [77]. Additionally, a decrease in secondary bile acids, such as GDCA and TUDCA, impairs IL-22 secretion, exacerbating local ovarian inflammation and metabolic imbalance [78].

Importantly, HA aggravates gut dysbiosis through AR-mediated regulation of the FKBP5 gene, promoting DNA hypomethylation and microbial imbalance. This HA-microbiota feedback loop further impairs metabolic homeostasis. Androgens also reshape bile acid profiles and intestinal immunity, further shifting microbial ecology toward pro-inflammatory taxa [79]. This creates a vicious cycle wherein gut dysbiosis and HA reinforce each other, jointly driving endocrine and metabolic dysfunction.

In summary, gut microbiota dysbiosis in obese PCOS is both a cause and consequence of metabolic imbalance, mediated through disrupted SCFA and bile acid metabolism, loss of barrier integrity, and androgen-induced microbial shifts. These findings highlight the potential of microbiota-centered therapies—such as probiotics, prebiotics, and fecal microbiota transplantation—to restore host–microbiota homeostasis and break the pathophysiological cycle of obesity-related PCOS.

The HPO axis plays a central role in regulating reproductive function by orchestrating the secretion of LH and FSH through the pulsatile release of GnRH. This process coordinates follicular development and sex hormone synthesis. Under physiological conditions, estradiol exerts positive feedback to induce a preovulatory LH surge, while negative feedback maintains hormonal homeostasis [80].

In PCOS, the frequency of GnRH pulses is pathologically elevated, preferentially enhancing LH secretion over FSH. This disrupts the FSH-mediated induction of CYP19A1 (aromatase), impairing the conversion of androgens to estrogens, and resulting in HA and follicular arrest—core features of PCOS pathophysiology [81].

Obesity exacerbates neuroendocrine dysregulation through multiple interrelated mechanisms. Leptin resistance and chronic hyperleptinemia overstimulate GnRH neurons via kisspeptin signaling, promoting excessive LH release and subsequent androgen overproduction [80, 82, 83]. Concurrently, hyperinsulinemia activates AgRP neurons and increases the expression of neuropeptide Y (NPY) and GABA, which synergistically upregulate hypothalamic kisspeptin and GnRH expression, further aggravating LH hypersecretion [84 –86]. Altered gut microbiota—characterized by reduced levels of secondary bile acids such as glycodeoxycholic acid (GDCA) and tauroursodeoxycholic acid (TUDCA)—impair the bile acid-IL-22 signaling axis, diminishing hypothalamic sensitivity to androgen feedback and accelerating GnRH pulse generation [78].

These convergent pathways disrupt the LH/FSH ratio, amplify ovarian androgen output, and impair folliculogenesis. Ultimately, obesity-induced neuroendocrine reprogramming intensifies HPO axis dysfunction, contributing to anovulation and reproductive failure in PCOS.

In summary, obesity-driven alterations in metabolic, endocrine, and microbial pathways converge to intensify HPO axis dysfunction in PCOS Figure 1. Further elucidation of the molecular crosstalk between adipokines, central neuronal circuits, and peripheral metabolites may reveal novel targets for neuromodulatory interventions aimed at restoring reproductive endocrine homeostasis in obese PCOS patients.

Dysregulated autophagy contributes to follicular arrest and metabolic dysfunction in obesity-associated PCOS. Preclinical studies suggest that pharmacological agents, TCM, and acupuncture modulate key autophagy-related pathways, potentially restoring cellular homeostasis.

CLGI, driven by adipokines, IR, and oxidative stress, plays a central role in the pathogenesis of obesity-related PCOS. Targeting inflammatory pathways has demonstrated potential in alleviating both metabolic abnormalities and reproductive dysfunction.

ERS contributes to the metabolic and reproductive dysfunctions in PCOS by promoting GC apoptosis and impairing follicular development. Therapeutic modulation of ERS has emerged as a promising strategy for restoring ovarian homeostasis.

Gut microbiota dysbiosis contributes to the metabolic, inflammatory, and reproductive abnormalities observed in obesity-related PCOS. Modulating the gut microbiota has thus emerged as a promising therapeutic strategy. This section outlines current strategies—nutritional, pharmacological, and TCM-based—that aim to restore microbial balance and alleviate PCOS.

HPO axis dysregulation is a central driver of hormonal imbalance, anovulation, and metabolic disturbances in PCOS. Therapeutic modulation of this axis shows promise, particularly in obese phenotypes. This section reviews pharmacological, TCM-derived, and acupuncture-based strategies aimed at restoring HPO axis homeostasis.