Effect and mechanism of resveratrol against polycystic ovary syndrome: a review.

Polycystic ovary syndrome (PCOS) is a complex, heterogeneous disease that is a primary cause of infertility among reproductive-aged women, which is characterized by clinical and/or biochemical hyperandrogenism (HA), ovulation dysfunction, and polycystic ovary morphology (PCOM) ( 1 ), alongside elevated luteinizing hormone (LH) levels and increased LH-to-follicle stimulating hormone (FSH) ratio ( 2 ). PCOS is further associated with metabolic comorbidities including obesity, insulin resistance (IR), type 2 diabetes T2D, and hepatic steatosis, collectively elevating cardiovascular risk ( 3 , 4 ). The reproductive-related implications encompass menstrual irregularities, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer ( 5 ). Globally, the age-standardized prevalence and annual incidence rates of PCOS in 2019 were 1,677.8 and 59.8 per 100,000, respectively, reflecting a 30.4% and 29.5% increase since 1990 ( 6 ). Despite prevalence and incidence rising, the pathogenesis of PCOS remains incompletely elucidated. HA and IR play crucial roles in the progression of the disease ( 7 ). In other words, HA and IR are not merely common clinical manifestations of PCOS but also central pathogenic drivers of the disease ( 8 ). However, due to the heterogeneity of PCOS population and inherent racial/ethnic variations, the existing diagnostic criteria struggle to achieve universal applicability across all global regions ( 9 ), hindering the development of targeted therapies. Current treatment for PCOS integrates lifestyle modifications with pharmacotherapy. Lifestyle optimization focuses on a balanced, nutrient-dense diet and regular physical exercise to prevent excessive weight gain, mitigate PCOS-related complications, and promote weight loss when necessary. Pharmacological strategies include metformin to improve IR and correct associated metabolic abnormalities, combined oral contraceptive pills (COCPs) for regulating menstrual cycles and HA, and if needed, anti-androgens for refractory HA ( 10 ). Fertility-focused therapies such as letrozole and clomiphene are employed for ovulation induction. Nevertheless, there medicine predominantly address symptom management and assisted fertility rather than curative outcomes ( 11 ). There are many adverse reactions including metformin-related gastrointestinal intolerance, COCPs discontinuation relapses, anti-androgen teratogenicity, and elevated miscarriage/multiple pregnancy risks with letrozole and clomiphene ( 12 – 14 ). Therefore, it is imperative to seek a novel drug with multi-target properties, no adverse effects on patients’ health, and potential therapeutic effects. Resveratrol, a natural polyphenolic compound found in plants such as peanuts, grapes, knotweed, and mulberries ( 15 ), demonstrates pleiotropic biological activities. Preclinical studies highlight its capacity to improve ovarian histomorphology, regulate sex hormones and gonadotropins, modulate glucose/lipid metabolism, and exert antioxidant/anti-inflammatory effects. Clinical evidence suggests resveratrol may improve ovarian volume, increase the rate of high-quality oocytes and embryos, decrease androgen and gonadotropin concentrations, angiogenic factor levels, and alleviate endoplasmic reticulum stress in PCOS patients ( 16 ). This review aims to investigate PCOS and its related basic and clinical research, summarizing the mechanism of resveratrol in improving PCOS, with the goal of providing a reference for clinical drug administration.

PCOS is fundamentally characterized by interconnected pathological axes encompassing dysregulated glucose-lipid metabolism (manifesting as IR and obesity), HA, chronic inflammation with oxidative stress, and ovulatory dysfunction. These core pathophysiological components exhibit intricate bidirectional crosstalk, operating through mutually reinforcing mechanisms that collectively perpetuate the syndrome’s phenotypic heterogeneity and clinical progression ( Figure 1 ). The accumulating preclinical and clinical evidence establishes resveratrol as a promising multi-target therapeutic agent for PCOS, offering potential advantages over conventional symptomatic management strategies. Its demonstrated efficacy in improving insulin sensitivity via reducing FINS by 31.8% and improving ISI by 66.3% in clinical trials, ameliorating dyslipidemia, reducing HA via decreasing testosterone and LH levels while increasing FSH, attenuating chronic inflammation and oxidative stress, restoring ovarian folliculogenesis and ovulation via normalizing estrous cycles and increasing high-quality oocyte rates, and modulating gut microbiota dysbiosis. Collectively, these actions target interconnected reproductive, metabolic, and inflammatory pathologies inherent to PCOS ( Figure 2 , Table 1 ). Crucially, resveratrol achieves these outcomes with a favorable safety profile, potentially circumventing the gastrointestinal intolerance associated with metformin, relapse risk after COCP discontinuation, and the teratogenicity concerns of anti-androgens. This pleiotropic activity underscores significant clinical utility, positioning resveratrol as a valuable adjunct or alternative therapeutic—particularly for patients intolerant to first-line agents or those seeking concurrent management of metabolic and reproductive sequelae. The relationship between pathological links of PCOS. The main molecular targets of resveratrol in regulating PCOS. In addition, to ensure all figures meet the highest quality/resolution standards, we are uploading a PDF file containing the images. Regulation of resveratrol in PCOS. “↑”, Upregulation; “↓”, Downregulation. Furthermore, future research should prioritize large-scale, long-term randomized controlled trials to definitively establish optimal dosing regimens, confirm sustained efficacy across diverse PCOS phenotypes—especially considering inherent heterogeneity and ethnic variations, and rigorously evaluate hard clinical endpoints such as live birth rates, prevention of T2D/cardiovascular events, and endometrial cancer risk reduction. Mechanistic studies should further delineate the relative contributions and potential synergies between its primary pathways—particularly SIRT1/AMPK, PI3K/Akt, and PPAR signaling—and evaluate its impact on specific patient subgroups stratified by biomarkers like AMH or gut microbial signatures. Concurrently, investigating the potential of resveratrol in combinatorial therapies, particularly with metformin where preliminary synergy exists, and exploring its role in adolescent PCOS management during pubertal transition represents critical translational avenues. Bridging the gap between robust mechanistic insights and definitive clinical validation through such integrated approaches is paramount to fully actualize resveratrol’s therapeutic potential and advance personalized clinical management for women with PCOS.

The gut microbiota, a complex ecosystem of commensal microorganisms, plays a pivotal role in modulating host metabolic homeostasis, hormonal regulation, and immune-inflammatory responses. Emerging data implicates gut dysbiosis—a disruption in microbial composition and function—in the pathogenesis of diverse diseases, including reproductive and gynecological disorders ( 118 ). In PCOS, dysbiosis compromises intestinal barrier integrity by disrupting tight junction proteins, leading to increased intestinal permeability and systemic translocation of bacterial endotoxins. This endotoxemia triggers chronic low-grade inflammation, elevating pro-inflammatory cytokines, which may disrupt insulin signaling and fatty acid metabolism, further exacerbating IR and lipid metabolism irregularities. A meta-analysis revealed that the most prevalent bacterial alterations in PCOS, including Bacteroidaceae , Coprococcus , Bacteroides , Prevotella , Lactobacillus , Parabacteroides , Escherichia/Shigella , and Faecalibacterium prausnitzii ( 119 ). Additional literature has discovered a depletion of Lachnospira and Prevotella , alongside an enrichment of Bacteroides , Parabacteroides , Lactobacillus , Fusobacterium and Escherichia/Shigella in women with PCOS ( 120 ). Likewise, an operational taxonomic unit (OTU3) within Bacteroides —sharing 99.2% sequence similarity with Bacteroides acidifaciens , a species inversely correlated with obesity—was markedly diminished in PCOS-like mouse models ( 121 ). These findings collectively elucidate that gut dysbiosis, marked by a decline in anti-inflammatory and short-chain fatty acid (SCFA)-producing bacteria, exacerbates metabolic and hormonal disturbances in PCOS. Resveratrol demonstrates prebiotic-like properties that rectify these microbial imbalances. Preclinical studies report that resveratrol increases Bacteroidetes and Actinobacteria while reducing Firmicutes at the phylum level ( 122 ), counteracting the Firmicutes/Bacteroidetes ratio elevation linked to obesity and IR. It also elevates Bifidobacteriaceae and suppresses Streptococcus at the family level ( 122 ). At the genus level, resveratrol enriches Lactobacillus and inhibits Enterobacter ( 122 ). Resveratrol suppresses the expression of lipogenic genes, including Gpat1 (glycerol-3-phosphate acyltransferase 1), Mogat (monoacylglycerol O-acyltransferase), and Pparg (PPAR-γ), through microbiota-dependent mechanisms. This inhibition normalizes hepatic and adipose lipid accumulation, restoring systemic lipid homeostasis ( 123 ). By modulating the relative abundance of Ruminococcus (a genus linked to fiber fermentation and SCFA production) and Clostridium (associated with bile acid metabolism), resveratrol enhances insulin signaling via IRS-1 phosphorylation while suppressing mTOR expression and hyperactivation. This dual action repairs insulin receptor sensitivity and ameliorates hyperglycemia ( 123 ). Resveratrol restores the integrity of the intestinal barrier by altering the composition of gut microbiota via upregulating the expression of tight junction proteins, zonula occludens-1 (ZO-1) and occluding. It also attenuates systemic inflammation caused by the enhancement of TLR4 and myeloid differentiation factor 88 (MyD88), suppressing the release of inflammatory factors such as TNF-α and IL-1. Resveratrol demonstrates the capacity to restructure gut microbiota composition, which may in turn alleviate the abnormal glucose/lipid metabolism, chronic inflammation, and oxidative stress associated with gut dysbiosis in PCOS pathogenesis.