Exploring the role of the NLRP3 Inflammasome in polycystic ovary syndrome: therapeutic potential of herbal medicines

The NLRP3 inflammasome acts as a molecular driver that connects inflammation with the metabolic dysfunction characteristic of PCOS [ 37 ]. Recent studies reported elevated expression and activation of the NLRP3 inflammasome in ovarian GCs from both PCOS patients and animal models [ 5 ]. This upregulation is associated with increased levels of IL-1β and IL-18, creating a pro-inflammatory environment in the ovaries that impairs follicle growth and ovulation [ 38 , 39 ]. Moreover, steroidogenic enzyme activity is disrupted by IL-1β that affects estrogen and progesterone synthesis and worsens hormonal imbalance [ 40 ]. One critical complication of PCOS is hyperandrogenism, which activates the NLRP3 inflammasome. Elevated androgen levels increase the expression of NLRP3 and ASC in GCs, enhancing inflammasome formation and cytokine release [ 36 ]. This process leads to a vicious cycle in which androgens promote inflammation, while inflammation in turn stimulates androgen production, results in disease progression. The resulting oxidative stress and fibrotic remodeling of ovarian tissue contribute to follicular arrest and ovarian cyst formation [ 41 , 42 ]. As mentioned above, IR is another major metabolic hallmark of PCOS in which inflammatory cytokines play a pivotal role. NLRP3 inflammasome activation contributes to this dysfunction by affecting insulin receptor substrates phosphorylation and disrupting downstream signaling in adipose tissue, muscle, and the liver [ 43 ]. Furthermore, IL-1β promotes macrophage infiltration into adipose tissue and polarizes macrophages toward a pro-inflammatory M1 phenotype, which amplifies local and systemic IR [ 44 ]. Animal studies confirm that NLRP3 genetic deletion or pharmacological inhibition can improve glucose tolerance and enhance insulin sensitivity [ 45 ]. The relationship between inflammation, obesity, and IR in PCOS is complex and bidirectional. While some studies have suggested that the inflammatory state may be exacerbated by coexisting obesity or IR [ 46 , 47 ], emerging evidence positions the NLRP3 inflammasome as a central molecular driver of low-grade chronic inflammation that is intrinsically linked to PCOS pathophysiology [ 5 , 37 ]. This creates a self-perpetuating cycle: metabolic disturbances such as IR and hyperandrogenism can activate the NLRP3 inflammasome (e.g., via elevated FFAs and oxidative stress) [ 43 , 44 ], and NLRP3-driven inflammation (e.g., via IL-1β) in turn worsens IR and hormonal imbalance [ 40 , 48 ]. Therefore, rather than being mutually exclusive, these factors are interconnected components of a vicious cycle that drives disease progression. This integrated model highlights the importance of targeting inflammation as a therapeutic strategy in PCOS, regardless of its initial trigger. Furthermore, one study revealed that alterations in the follicular microenvironment can activate inflammatory pathways, impair GCs’ proliferative capacity, and exacerbate oocyte maturation arrest [ 49 ] (Fig. 1 ). Taken together, these findings highlight the NLRP3 inflammasome as a central molecular link between chronic inflammation, metabolic dysfunction, and ovarian abnormalities in PCOS [ 5 , 37 ]. Given the NLRP3 inflammasome pivotal role in the PCOS pathophysiology, identifying modulating therapeutic agents on this pathway has become an interesting area of research [ 40 ]. Some natural bioactive compounds have emerged as promising candidates as well as pharmacological medicines. They offer the potential to suppress excessive inflammasome activation and regulate NLRP3 activation [ 50 , 51 ]. Therefore, understanding the NLRP3 inflammasome dysregulation provides a strong rationale for exploring herbal medicine-based interventions as potential therapeutic strategies for PCOS which will be discussed in the continuation. Fig. 1 Schematic representation of the NLRP3 inflammasome pathway in Polycystic Ovary Syndrome (PCOS) pathophysiology and the modulatory role of herbal medicines. The NLRP3 inflammasome pathway plays an important role in the pathophysiology of PCOS. This pathway is initiated during the priming step when Toll-like Receptors (TLRs) are activated by Damage- or Pathogen-associated Molecular Patterns (DAMPs and PAMPs), which then stimulate NF-κB signaling and increase the expression of NLRP3 and pro-IL-1β. In the activation step, several cellular events occur, including Potassium (K⁺) and Calcium (Ca²⁺) efflux, excessive Reactive Oxygen Species (ROS) formation, and mitochondrial dysfunction. The activated NLRP3 complex converts procaspase-1 into active caspase-1, which subsequently processes pro-IL-1β and pro-IL-18 into their active cytokine forms. Herbal medicines can reduce this inflammatory process by enhancing antioxidant defense systems, decreasing mitochondrial ROS, and suppressing NLRP3 inflammasome activation. This figure was created by the authors using BioRender.com Schematic representation of the NLRP3 inflammasome pathway in Polycystic Ovary Syndrome (PCOS) pathophysiology and the modulatory role of herbal medicines. The NLRP3 inflammasome pathway plays an important role in the pathophysiology of PCOS. This pathway is initiated during the priming step when Toll-like Receptors (TLRs) are activated by Damage- or Pathogen-associated Molecular Patterns (DAMPs and PAMPs), which then stimulate NF-κB signaling and increase the expression of NLRP3 and pro-IL-1β. In the activation step, several cellular events occur, including Potassium (K⁺) and Calcium (Ca²⁺) efflux, excessive Reactive Oxygen Species (ROS) formation, and mitochondrial dysfunction. The activated NLRP3 complex converts procaspase-1 into active caspase-1, which subsequently processes pro-IL-1β and pro-IL-18 into their active cytokine forms. Herbal medicines can reduce this inflammatory process by enhancing antioxidant defense systems, decreasing mitochondrial ROS, and suppressing NLRP3 inflammasome activation. This figure was created by the authors using BioRender.com

Inflammatory processes can proceed through the canonical pathway, in which activation of the NLRP3 inflammasome facilitates its interaction with the adaptor protein ASC, leading to recruitment and cleavage of pro–caspase-1 into its active form. Activated caspase-1 subsequently cleaves gasdermin D (GSDMD), releasing an N-terminal fragment that translocates to the plasma membrane, disrupts membrane integrity, and triggers cell lysis [ 108 , 109 ]. This inflammatory milieu promotes pyroptotic cell death, which in turn compromises oocyte quality and adversely influences reproductive outcomes [ 110 ]. Supporting this, Ibrahim et al. demonstrated that the NLRP3/caspase-1 signaling axis is upregulated in letrozole-induced rat models of PCOS [ 111 ]. Recent research has increasingly confirmed the pivotal role of NLRP3 inflammasome signaling in PCOS pathophysiology. Moreover, natural products derived from medicinal plants, dietary components, animals, and microorganisms have shown promise in modulating pyroptosis through diverse molecular targets, offering significant potential for improving female reproductive health [ 112 – 114 ] (see Table 1 ). Given the central role of NLRP3 inflammasome activation in the development of chronic inflammation, insulin resistance, granulosa cell dysfunction, and pyroptosis in PCOS, therapeutic strategies targeting this pathway have attracted increasing research interest. In recent years, several herbal medicines and naturally derived phytochemicals have demonstrated the ability to modulate NLRP3 inflammasome signaling and its downstream inflammatory mediators in experimental models [ 103 , 115 ]. Therefore, these compounds may represent promising adjunctive approaches for mitigating the metabolic and reproductive abnormalities associated with PCOS. Table 1 The effect of different herbal medicine on PCOS through suppressing NLRP3 pathways Drug/Herb Name Active Compounds Study Model Pathway/Mechanism Biological/Clinical Effects Anti-inflammatory Effects Pyroptosis Effects Key Findings Rubus chingii Hu Flavonoids, Tannins, Polyphenols In vivo: Female rat model of PCOS Inhibition of the TXNIP/NLRP3 signaling pathway. R. chingii  suppresses the activation of the thioredoxin-interacting protein (TXNIP), which in turn inhibits the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in ovarian tissue. Hormonal Balance: Reduction of Luteinizing Hormone (LH) and Testosterone (T) levels. Metabolic Health: Improvement of IR, evidenced by decreased HOMA-IR scores. Ovarian Function: Amelioration of ovarian pathology and reduction of atretic follicles. Reduction of systemic inflammation: Significant decrease in C-reactive protein (CRP) levels following treatment. Inhibition of Pyroptosis initiation: By blocking the TXNIP/NLRP3 inflammasome activation,  R. chingii  likely prevents the downstream cascade (Caspase-1, Gasdermin D (GSDMD)) R. chingii  alleviates hormone imbalance and IR in PCOS rats by inhibiting the TXNIP/NLRP3 inflammasome pathway. Formononetin FMN (Isoflavonoid) In vivo : Rat model of PCOS In vitro: Human granulosa-like tumor cells or rat ovarian GCs under oxidative/inflammatory stress. Inhibition of the NLRP3 inflammasome signaling pathway. FMN suppresses the activation of the inflammasome complex by downregulating the expression of key genes, including NLRP3, ASC, and Caspase-1. - Improvement of Ovarian Function: Reduction in the number of cystic follicles and an increase in healthy follicles. - Hormonal Balance: Decrease in serum levels of LH and T. - Metabolic Improvement: Alleviation of IR (evidenced by reduced HOMA-IR scores). Significant reduction of pro-inflammatory cytokines: Decrease in the levels of IL-1β and IL-18, which are directly regulated by the NLRP3 inflammasome. Inhibition of Pyroptosis: By inhibiting Caspase-1, FMN prevents the cleavage of GSDMD. FMN ameliorates PCOS by suppressing the NLRP3 inflammasome pathway, leading to reduced ovarian inflammation and IR. This compound shows strong therapeutic potential for improving PCOS symptoms through the inhibition of inflammatory cell death (pyroptosis). Mogroside V MV (Cucurbitane glycoside) In vivo: female rat model of PCOS Promotion of the Glycolytic Pathway. MV restores glycolytic function by upregulating key enzymes, including lactate dehydrogenase A (LDHA), hexokinase 2 (HK2), and pyruvate kinase M2 (PKM2) in ovarian GCs. Metabolic Improvement: Reduced body weight and ovary weight; decreased testosterone levels; increased levels of D-Glucose 6-phosphate, lactate, and GTP; decreased pyruvate levels. Ovarian Function: Restored disrupted estrous cycles; improved follicular development by increasing the number of corpora lutea and the thickness of the granulosa cell layer. Not directly investigated in this study. Not investigated in this study. MV improves the ovarian microenvironment in PCOS rats by upregulating the expression of glycolytic enzymes (LDHA, HK2, PKM2) in GCs. This enhances lactate and energy production, contributing to improved follicle development and ovulation. C-Phycocyanin C- PC (Phycobiliprotein) In vivo: Female mouse model of PCOS In vitro: granulosa cell pyroptosis model. Regulation of the NRF2/NLRP3/GSDMD and ROS/p38-MAPK pathways. C-PC activates NRF2, which inhibits NLRP3 inflammasome activation. This reduces cleaved caspase-1 and N-GSDMD (the executer of pyroptosis). C-PC also suppresses ROS/p38-MAPK activation induced by DHEA. Hormonal Balance: Reduced serum testosterone levels. Ovarian Function: Restored the estrous cycle; decreased the number of cystic follicles; improved ovarian morphology. Cellular Protection: Reduced oxidative stress levels in GCs. Reduction of pro-inflammatory cytokines: C-PC inhibits NLRP3 inflammasome activation, which subsequently reduces the release of IL-1β and IL-18 Inhibition of Pyroptosis: C-PC suppresses granulosa cell pyroptosis by: 1. Blocking NLRP3 inflammasome activation. 2. Reducing N-GSDMD formation (the pore-forming protein). 3. Preventing DHEA-induced cell membrane pore formation (observed by SEM). C-PC effectively attenuates PCOS progression by inhibiting ovarian granulosa cell pyroptosis through activation of the NRF2 pathway and suppression of the NLRP3/GSDMD axis. Molecular docking suggests C-PC may also indirectly bind to the Ser27 site of GSDMD. This natural compound shows therapeutic potential for PCOS by targeting inflammatory cell death pathways Resveratrol Resveratrol (3,4’,5-trihydroxystilbene) In vivo: Female rat model of PCOS In vitro: Primary rat ovarian GCs. Inhibition of NLRP3 inflammasome and pyroptosis pathways. Resveratrol downregulates the expression of key pyroptosis-related proteins, including NLRP3, Cleaved-Caspase-1, and N-GSDMD. The mechanism is likely mediated by reducing oxidative stress and inflammatory signaling. Hormonal Balance: Decreased serum levels of T, LH, and Anti-Müllerian Hormone (AMH); increased E2 levels. Ovarian Function: Restored estrous cyclicity; reduced the number of atretic follicles; improved ovarian morphology. Metabolic: Reduced body weight gain. Reduction of pro-inflammatory cytokines: Resveratrol significantly decreased levels of IL-1β and IL-18 both in serum and in granulosa cell culture supernatants. Inhibition of Pyroptosis: Resveratrol suppressed DHEA-induced pyroptosis in GCs by: 1. Downregulating NLRP3 inflammasome activation. 2. Reducing Cleaved-Caspase-1 expression. 3. Decreasing N-GSDMD formation (the pore-forming protein) . 4. Reducing LDH release and cell death. Resveratrol effectively improves follicular development in PCOS rats by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway in ovarian GCs. This natural compound reduces inflammatory cell death, restores ovarian function, and corrects hormonal imbalances, suggesting its therapeutic potential for PCOS treatment. Paeoniae Radix Alba Paeoniflorin, Albiflorin, Paeoniflorigenone, β-Sitosterol, Kaempferol, (+)-Catechin In vitro: Human THP-1 monocytes Regulation of TLR2/4 and NLRP3 inflammasome signaling pathways. Catechin suppresses the expression of Toll-like receptors TLR2 and TLR4, which inhibits the downstream NF-κB pathway. It also inhibits the activation of the NLRP3 inflammasome. Periodontal health: Reduces inflammation in gingival tissues by targeting bacterial components. Cellular protection: Protects macrophages from excessive inflammatory responses induced by periodontal pathogens. Significant reduction of pro-inflammatory cytokines: Catechin decreases the expression of IL-1β, IL-6, TNF-α, and IL-8 in a dose-dependent manner. The most effective inhibition was observed at concentrations of 25–50 µM . Inhibition of NLRP3 inflammasome activation: Catechin suppresses the expression of NLRP3, ASC, and Caspase-1, thereby reducing the production of mature IL-1β. Catechin effectively attenuates  Porphyromonas gingivalis -induced inflammation by simultaneously targeting two key pathways: (1) TLR2/4-mediated NF-κB signaling (the priming signal) and (2) NLRP3 inflammasome activation (the activation signal). The effect of different herbal medicine on PCOS through suppressing NLRP3 pathways In vivo: Female rat model of PCOS Inhibition of the TXNIP/NLRP3 signaling pathway. R. chingii  suppresses the activation of the thioredoxin-interacting protein (TXNIP), which in turn inhibits the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in ovarian tissue. Hormonal Balance: Reduction of Luteinizing Hormone (LH) and Testosterone (T) levels. Metabolic Health: Improvement of IR, evidenced by decreased HOMA-IR scores. Ovarian Function: Amelioration of ovarian pathology and reduction of atretic follicles. In vivo : Rat model of PCOS In vitro: Human granulosa-like tumor cells or rat ovarian GCs under oxidative/inflammatory stress. Inhibition of the NLRP3 inflammasome signaling pathway. FMN suppresses the activation of the inflammasome complex by downregulating the expression of key genes, including NLRP3, ASC, and Caspase-1. - Improvement of Ovarian Function: Reduction in the number of cystic follicles and an increase in healthy follicles. - Hormonal Balance: Decrease in serum levels of LH and T. - Metabolic Improvement: Alleviation of IR (evidenced by reduced HOMA-IR scores). Significant reduction of pro-inflammatory cytokines: Decrease in the levels of IL-1β and IL-18, which are directly regulated by the NLRP3 inflammasome. Inhibition of Pyroptosis: By inhibiting Caspase-1, FMN prevents the cleavage of GSDMD. In vivo: female rat model of PCOS Promotion of the Glycolytic Pathway. MV restores glycolytic function by upregulating key enzymes, including lactate dehydrogenase A (LDHA), hexokinase 2 (HK2), and pyruvate kinase M2 (PKM2) in ovarian GCs. Metabolic Improvement: Reduced body weight and ovary weight; decreased testosterone levels; increased levels of D-Glucose 6-phosphate, lactate, and GTP; decreased pyruvate levels. Ovarian Function: Restored disrupted estrous cycles; improved follicular development by increasing the number of corpora lutea and the thickness of the granulosa cell layer. In vivo: Female mouse model of PCOS In vitro: granulosa cell pyroptosis model. Regulation of the NRF2/NLRP3/GSDMD and ROS/p38-MAPK pathways. C-PC activates NRF2, which inhibits NLRP3 inflammasome activation. This reduces cleaved caspase-1 and N-GSDMD (the executer of pyroptosis). C-PC also suppresses ROS/p38-MAPK activation induced by DHEA. Hormonal Balance: Reduced serum testosterone levels. Ovarian Function: Restored the estrous cycle; decreased the number of cystic follicles; improved ovarian morphology. Cellular Protection: Reduced oxidative stress levels in GCs. Reduction of pro-inflammatory cytokines: C-PC inhibits NLRP3 inflammasome activation, which subsequently reduces the release of IL-1β and IL-18 Inhibition of Pyroptosis: C-PC suppresses granulosa cell pyroptosis by: 1. Blocking NLRP3 inflammasome activation. 2. Reducing N-GSDMD formation (the pore-forming protein). 3. Preventing DHEA-induced cell membrane pore formation (observed by SEM). In vivo: Female rat model of PCOS In vitro: Primary rat ovarian GCs. Inhibition of NLRP3 inflammasome and pyroptosis pathways. Resveratrol downregulates the expression of key pyroptosis-related proteins, including NLRP3, Cleaved-Caspase-1, and N-GSDMD. The mechanism is likely mediated by reducing oxidative stress and inflammatory signaling. Hormonal Balance: Decreased serum levels of T, LH, and Anti-Müllerian Hormone (AMH); increased E2 levels. Ovarian Function: Restored estrous cyclicity; reduced the number of atretic follicles; improved ovarian morphology. Metabolic: Reduced body weight gain. Reduction of pro-inflammatory cytokines: Resveratrol significantly decreased levels of IL-1β and IL-18 both in serum and in granulosa cell culture supernatants. Inhibition of Pyroptosis: Resveratrol suppressed DHEA-induced pyroptosis in GCs by: 1. Downregulating NLRP3 inflammasome activation. 2. Reducing Cleaved-Caspase-1 expression. 3. Decreasing N-GSDMD formation (the pore-forming protein) . 4. Reducing LDH release and cell death. In vitro: Human THP-1 monocytes Regulation of TLR2/4 and NLRP3 inflammasome signaling pathways. Catechin suppresses the expression of Toll-like receptors TLR2 and TLR4, which inhibits the downstream NF-κB pathway. It also inhibits the activation of the NLRP3 inflammasome. Periodontal health: Reduces inflammation in gingival tissues by targeting bacterial components. Cellular protection: Protects macrophages from excessive inflammatory responses induced by periodontal pathogens. Significant reduction of pro-inflammatory cytokines: Catechin decreases the expression of IL-1β, IL-6, TNF-α, and IL-8 in a dose-dependent manner. The most effective inhibition was observed at concentrations of 25–50 µM . Inhibition of NLRP3 inflammasome activation: Catechin suppresses the expression of NLRP3, ASC, and Caspase-1, thereby reducing the production of mature IL-1β. A growing body of evidence suggests that several phytochemicals can modulate NLRP3 inflammasome activity through diverse molecular mechanisms. The following sections summarize the current evidence regarding selected herbal compounds that have demonstrated potential benefits in experimental models of PCOS. Rubus chingii Hu (R. chingii), commonly referred to as raspberry [ 116 ], possesses a diverse range of biological and pharmacological activities, including enhancement of cognitive function, anti-aging effects, anti-inflammatory and anti-tumor actions, immunomodulatory properties, and potent antioxidant capacity [ 117 , 118 ]. Owing to these attributes, R. chingii has demonstrated therapeutic potential across multiple disease domains and represents a promising candidate for further pharmacological development. Notably, R. chingii has been reported to alleviate PCOS by improving insulin sensitivity through inhibition of the TXNIP/NLRP3 inflammasome pathway [ 119 ]. Evidence supporting this effect is currently limited to preclinical animal studies (PCOS rat models), and no clinical trials in women with PCOS have yet been reported. Its antioxidant properties have also been confirmed in the kidneys and serum of aging mouse models [ 120 ]. In a PCOS rat model, R. chingii administration (orally at doses ranging from approximately 10 mg/kg/day for 28 days) increased insulin receptor substrate-1 (IRS-1) expression, an effect likely linked to reduced TXNIP/NLRP3 inflammasome activity. Conversely, TXNIP overexpression abrogated the improvements in IR and hormonal dysregulation conferred by R. chingii treatment, underscoring the importance of TXNIP/NLRP3 modulation in its therapeutic action [ 118 , 119 ]. However, no standardized human-equivalent dose has been established. Overall, current evidence suggests that R. chingii may ameliorate PCOS-associated metabolic and inflammatory disturbances through modulation of the TXNIP/NLRP3 inflammasome pathway. However, these findings are derived exclusively from preclinical animal models, and their direct translation to human PCOS remains uncertain due to species-specific differences in metabolism, endocrine regulation, and inflammatory responses. Furthermore, evidence regarding the effects of R. chingii on NLRP3 inflammasome signaling in women with PCOS is currently lacking, and no clinical trials have evaluated its efficacy, safety, or optimal dosing. Therefore, further mechanistic studies and well-designed randomized controlled trials are required to validate its therapeutic potential and clarify the role of NLRP3 modulation in its clinical effects. Formononetin (FMN), a major isoflavonoid constituent primarily derived from Astragalus membranaceus , exhibits potent anti-inflammatory, anti-apoptotic, and antioxidant effects across a variety of pathological conditions [ 121 ]. These include cerebral ischemia–reperfusion injury [ 122 ], atherosclerosis [ 123 ], oxaliplatin-induced peripheral neuropathy [ 124 ], diabetic nephropathy [ 125 ], and inflammatory bowel disease [ 126 ], mediated through modulation of multiple signaling pathways. Increasing evidence has also highlighted FMN’s relevance to women’s reproductive health. For instance, FMN suppresses the progression of endometriosis [ 127 ], enhances in vitro fertilization outcomes [ 128 ], and inhibits ovarian cancer cell proliferation and metastasis [ 129 ]. According to Liu et al., FMN was administered to PCOS rat models at doses of 15, 30, and 60 mg/kg/day (oral gavage) for 21 days, resulting in significant improvement in ovarian morphology, hormonal imbalance, oxidative stress markers, and suppression of NLRP3 inflammasome activation. In vitro, FMN was applied to GCs at micromolar concentrations that effectively reduced inflammasome-related protein expression [ 130 ]. However, no validated human-equivalent dose or standardized clinical dosing regimen has yet been established. FMN treatment reversed DHEA- and DHT-induced upregulation of NLRP3, ASC, and caspase-1 expression in both in vivo and in vitro models. Functional rescue experiments further revealed that nigericin, a known NLRP3 activator, abolished the beneficial effects of FMN on apoptosis, inflammation, and oxidative stress in DHT-induced PCOS GCs, underscoring the pivotal role of NLRP3 suppression in FMN’s therapeutic action [ 130 ]. Collectively, the available evidence suggests that FMN may exert protective effects against PCOS by attenuating oxidative stress, inflammation, and granulosa cell dysfunction through inhibition of NLRP3 inflammasome signaling. However, the current evidence is restricted to animal and cell-based studies, and the extent to which these findings can be translated to women with PCOS remains uncertain. Differences in pharmacokinetics, endocrine regulation, and inflammatory responses between experimental models and humans may influence therapeutic outcomes. Furthermore, no clinical trials have evaluated the efficacy, safety, pharmacokinetics, or optimal dosing of FMN in women with PCOS. Therefore, additional mechanistic studies and well-designed randomized controlled trials are required to validate the role of NLRP3 modulation in the therapeutic effects of FMN and to determine its clinical applicability in PCOS management. Mogroside V (MV), the principal bioactive compound of Siraitiae Fructus , exhibits a broad spectrum of pharmacological activities, including hypoglycemic, lipid-lowering, antioxidant, and anti-fatigue effects. In addition, MV has been shown to possess anti-inflammatory properties, enhance pulmonary function, protect the nervous system, exert anticancer effects, support reproductive function [ 131 ], and reduce intracellular ROS levels [ 132 ]. Recent studies indicate that MV contributes to normal follicular development, delays oocyte aging [ 133 ], facilitates porcine oocyte maturation [ 134 ], and protects intestinal epithelial barrier integrity in ulcerative colitis models by reducing inflammatory mediators in both in vivo and in vitro systems [ 135 ]. Preliminary evidence suggests that the reproductive benefits of MV are closely related to its antioxidant activity and enhancement of mitochondrial function, with sirtuin 1 (SIRT1) identified as a key regulatory molecule [ 133 , 136 ]. Moreover, MV has been reported to protect the intestine from heat stress–induced damage by mitigating inflammation and oxidative stress [ 137 ] and to preserve ovarian reserve in aging mice by reducing inflammatory stress [ 138 ]. In the context of PCOS, MV (600 mg/kg/day, orally, for 30 days) ameliorates ovarian metabolic dysfunction by modulating the expression of critical glycolytic enzymes, thereby improving ovarian morphology, restoring physiological function, and enhancing fertility outcomes in preclinical in vivo evidence (letrozole- and high-fat diet–induced PCOS rat models) [ 139 ]. In PCOS rat models, ovaries and GCs exhibited an inflammatory phenotype characterized by elevated pyroptosis-associated factors, which were significantly reduced following 600 mg/kg/d MV administration for 30 days [ 140 ]. Clinical observations similarly show that PCOS patients experience chronic low-grade inflammation, with increased expression of NLRP3 inflammasome components and other pro-inflammatory mediators [ 141 ]. This inflammatory state is strongly associated with dysregulated glucose and lipid metabolism, creating a pathological feedback loop in which chronic inflammation and metabolic disturbances mutually exacerbate one another. This cycle drives abnormal follicular development, hyperandrogenism, reduced insulin sensitivity, and persistent ovulatory dysfunction in PCOS [ 141 ]. However, no randomized controlled clinical trials in women with PCOS have been reported to date. In obesity-related metabolic dysfunction, NLRP3 activation is a critical driver of systemic inflammation and impaired insulin signaling [ 45 ]. Abnormal follicular development remains a fundamental cause of persistent ovulatory dysfunction and endocrine abnormalities in PCOS patients. Follicular maturation is a finely regulated process involving coordinated interactions among the oocyte, GCs, and theca cells [ 142 ]. Within this microenvironment, GCs communicate bidirectionally with oocytes and are modulated by oocyte-secreted factors; therefore, granulosa cell gene expression and function serve as important indicators of oocyte developmental potential. Because of their physiological relevance, GCs are frequently used in vitro to investigate PCOS pathogenesis [ 143 , 144 ]. Hyperinsulinemia resulting from IR, as well as androgen fluctuations, significantly impacts granulosa cell function [ 145 , 146 ]. Taken together, the available evidence indicates that MV may improve ovarian function, insulin sensitivity, and follicular development in PCOS through suppression of inflammasome-associated pyroptosis and attenuation of chronic inflammation. However, these findings are based predominantly on preclinical animal studies, and their direct applicability to women with PCOS remains uncertain due to species-specific differences in metabolism, endocrine regulation, and ovarian physiology. In addition, the mechanistic evidence linking MV to NLRP3 inflammasome modulation in PCOS is currently limited and requires further validation in clinically relevant models. Furthermore, no randomized controlled clinical trials have evaluated the efficacy, safety, long-term outcomes, or optimal dosing of MV in women with PCOS. Therefore, additional mechanistic investigations and well-designed clinical studies are needed to confirm its therapeutic potential and clarify the contribution of NLRP3-related pathways to its effects in PCOS. C-Phycocyanin (C-PC) is a phycobiliprotein predominantly derived from blue-green algae, including Spirulina platensis, with well-documented antioxidant, neuroprotective, and free radical-scavenging activities [ 147 , 148 ]. These properties position C-PC as a promising candidate for mitigating ROS-mediated aging and oxidative damage [ 149 , 150 ]. As a water-soluble pigment, C-PC is widely utilized as a dietary supplement across multiple countries [ 151 ]. Beyond its nutritional value, C-PC demonstrates diverse pharmacological activities, including hepatoprotective [ 152 ] and antiarthritic effects [ 153 ]. Importantly, its anti-inflammatory potential has been observed in numerous experimental models [ 154 – 156 ], largely through the inhibition of cyclooxygenase-2 (COX-2) activity [ 157 ]. A mechanistic study indicated that C-PC attenuates inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages by preventing the degradation of cytosolic IκB-α, thereby suppressing NF-κB pathway activation [ 156 ]. In in vivo models of PCOS demonstrated that C-PC (100 mg/kg/day) administered for 4 weeks reduced NLRP3 and GSDMD expression and alleviates disease progression by inhibiting granulosa cell pyroptosis via NRF2 activation. In vitro experiments further demonstrate that C-PC protects GCs from DHEA-induced cytotoxicity by lowering ROS levels, suppressing pyroptotic pathways, and modulating the ROS/p38-MAPK signaling cascade [ 158 ]. Also, there is currently no consensus on a safe and effective dose for humans or a standardized method for its clinical use. Available evidence supports the potential role of C-PC in attenuating PCOS-related inflammation and granulosa cell pyroptosis through modulation of the NRF2/ROS/NLRP3 signaling axis. However, the current body of evidence is restricted to in vitro experiments and animal studies, and the extent to which these findings can be translated to women with PCOS remains uncertain. Differences in pharmacokinetics, bioavailability, endocrine regulation, and inflammatory responses between experimental models and humans may influence therapeutic efficacy. In addition, the mechanistic evidence linking C-PC-mediated NLRP3 inhibition to clinical improvement in PCOS remains limited and requires further validation in human studies. Moreover, no clinical trials have systematically evaluated the efficacy, safety, long-term outcomes, or optimal dosing of C-PC in women with PCOS. Therefore, well-designed clinical studies are needed to confirm its therapeutic potential and establish its translational relevance in PCOS management. Resveratrol (3,4′,5-trihydroxystilbene) is a naturally occurring phytoalexin recognized for its nutraceutical potential and therapeutic applications across a spectrum of diseases [ 159 ]. An in vitro study indicates that resveratrol can suppress androgen biosynthesis and downregulate Cyp17a1 mRNA expression in rat theca-interstitial cells by inhibiting Akt/PKB phosphorylation [ 160 ]. Additionally, it modulates steroidogenesis through the suppression of steroidogenic acute regulatory protein and cytochrome P450c17 expression [ 161 ]. Wong et al. further demonstrated that resveratrol at concentrations of 30–100 µM inhibits theca-interstitial cell proliferation while promoting apoptosis, consistent with its role as an apoptotic effector by activating caspases 3 and 7, inducing DNA fragmentation, and eliciting characteristic morphological changes in a rat model [ 162 ]. In rodent models of PCOS, resveratrol has emerged as a promising agent for complementary or alternative therapeutic strategies. Treatment with 15 µM resveratrol significantly reduced ROS production and suppressed pro-inflammatory cytokine expression in LPS-stimulated KGN cells. Moreover, resveratrol downregulated pyroptosis-related proteins, including GSDMD and cleaved Caspase-1, while attenuating IL-18 and IL-1β secretion. Morphological assessments further confirmed that resveratrol mitigated LPS-induced pyroptotic alterations in KGN cells. Collectively, these findings suggest that resveratrol may support follicular development in PCOS by inhibiting inflammation and NLRP3/GSDMD/Caspase-1-mediated pyroptosis in ovarian GCs, highlighting its potential as a novel therapeutic intervention for PCOS [ 163 ]. Although the available preclinical and clinical evidence suggests that resveratrol may improve both metabolic and endocrine abnormalities in PCOS, several limitations should be considered. Most mechanistic evidence regarding NLRP3 inflammasome inhibition and pyroptosis suppression has been derived from in vitro and animal studies, and it remains unclear whether these molecular effects are reproducible in women with PCOS. While preliminary clinical trials have reported beneficial effects on androgen levels and insulin sensitivity, the direct impact of resveratrol on NLRP3 inflammasome activity has not been evaluated in human subjects. Furthermore, the number of clinical studies remains limited, with relatively small sample sizes and short follow-up periods. Therefore, larger well-designed randomized controlled trials are required to confirm its long-term efficacy, safety, optimal dosing, and the clinical relevance of NLRP3 modulation in PCOS management. Paeoniae Radix Alba (PRA) has been traditionally employed to alleviate pain, calm the liver and regulate liver yang [ 164 ]. PRA mitigates hepatotoxicity induced by the common three-wingnut root by attenuating oxidative stress [ 165 ]. Among its bioactive constituents, paeoniflorin exerts hepatoprotective effects against LPS-induced acute liver injury by preventing mitochondrial dysfunction and inhibiting NLRP3 inflammasome activation via the SIRT3/FOXO1a/SOD1 signaling pathway [ 166 ]. PRA has therefore emerged as an important modulator in the context of liver disease, where the liver and immune system collaborate to protect against pathogenic insults. Inflammasomes, cytoplasmic multiprotein complexes comprising nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), ASC, and pro-caspase-1, act as crucial innate immune sensors that maintain cellular homeostasis [ 164 ]. They are activated by PAMPs and DAMPs [ 167 ]. Several pattern recognition receptors (PRRs), including NLRP1, NLRP3, AIM2, NLRC4, and IFI16, are capable of forming inflammasomes, with NLRP3 being the most extensively studied [ 168 ]. Upon activation, NLRP3 recruits ASC and pro-caspase-1, leading to the cleavage of pro-IL-1β and pro-IL-18 and subsequent secretion of pro-inflammatory cytokines IL-1β and IL-18 [ 169 , 170 ]. Dysregulated inflammasome activity is a key contributor to liver disease and a significant risk factor for drug-induced liver injury (DILI). PRA contains eight bioactive ingredients with notable anti-inflammatory properties. Among these, the monoterpenes paeoniflorigenone, paeoniflorin, and albiflorin exhibit potent inhibition of TNF-α-induced endothelial cell damage [ 171 , 172 ]. Paeoniflorin also normalizes aberrant inflammatory signaling pathways and modulates immune cell function in conditions such as rheumatoid arthritis and psoriasis [ 173 ]. Albiflorin attenuates anxiety, neuropathic pain, and depressive-like behaviors by suppressing NLRP3 inflammasome activity in rodent models [ 174 ]. β-Sitosterol, a phytosterol, reduces adipocyte-mediated inflammation and lowers IL-6 and TNF-α levels by downregulating JNK and IKKβ/NF-κB signaling. In high-fat diet-induced intestinal inflammation models, it inhibits NF-κB nuclear translocation and prevents LPS-TLR4 interactions [ 175 , 176 ]. Kaempferol has been shown to decrease I-κB and NF-κB expression in LPS-stimulated in vitro models of inflammatory bowel disease [ 177 ], while (+)-catechin modulates TLR2/4, MAPK, and NF-κB signaling in mice challenged with Porphyromonas Gingivalis [ 178 ]. Collectively, these findings underscore the anti-inflammatory potential of PRA constituents, supporting their utility in managing conditions such as PCOS. PRA has been frequently used to alleviate PCOS-related symptoms, including elevated LH, testosterone, and estradiol levels, while improving ovarian function [ 179 ]. Collectively, these findings highlight the anti-inflammatory and immunomodulatory potential of PRA constituents; however, it should be emphasized that most mechanistic evidence has been derived from experimental models of inflammatory and metabolic diseases other than PCOS. Therefore, the direct relevance of these pathways to PCOS pathophysiology and NLRP3 inflammasome activation in the ovarian microenvironment remains largely speculative. Although PRA has been traditionally used and is reported to improve certain hormonal and ovarian parameters in PCOS, robust mechanistic and clinical evidence supporting its efficacy in this condition is still limited. In particular, no high-quality randomized controlled clinical trials have evaluated its efficacy, safety, optimal dosing, or long-term outcomes in women with PCOS. Accordingly, further well-designed translational studies and clinical trials are required to clarify its therapeutic potential and its role in modulating NLRP3-related inflammation in PCOS.

This narrative review was conducted to summarize the current evidence regarding the role of the NLRP3 inflammasome in the pathophysiology of PCOS and to evaluate the potential therapeutic effects of herbal medicines targeting this inflammatory pathway. A comprehensive literature search was performed in PubMed, Scopus, and Web of Science from January 2000 to January 2026. The search strategy combined the following keywords and their related terms: “polycystic ovary syndrome” OR “PCOS”, “NLRP3 inflammasome”, “inflammasome”, “herbal medicine”, “phytotherapy”, “medicinal plants”, “natural products”, and “inflammation”. Eligible studies included original research articles, experimental in vitro and in vivo studies, animal studies, clinical studies, and relevant review articles investigating inflammasome-related mechanisms and herbal interventions in PCOS or related metabolic and reproductive disorders. Articles were screened based on relevance to the study objectives, and reference lists of selected publications were manually searched to identify additional eligible studies.

PCOS remains a complex and prevalent endocrine disorder with profound implications for women’s health. The involvement of the NLRP3 inflammasome in the pathophysiology of PCOS underscores the need for targeted therapeutic strategies that address the underlying inflammatory processes. Herbal medicines represent a promising therapeutic strategy, with the potential to modulate NLRP3 activation and improve clinical outcomes in women with PCOS. As we advance our understanding of the interplay between inflammation and metabolic dysfunction in PCOS, integrating traditional herbal knowledge with contemporary scientific research will be essential in developing innovative and effective treatment modalities. Future studies should prioritize the exploration of these natural compounds to ultimately enhance the quality of life for women affected by this challenging condition.

PCOS is a prevalent endocrine disorder that primarily affects women of reproductive age, with a global prevalence ranging between 6% and 20% among this population [ 6 , 7 ]. Initially, Stein and Leventhal characterized PCOS as a syndrome involving oligo-amenorrhea and polycystic ovaries [ 8 ]. It is recognized as a leading cause of menstrual irregularities, hirsutism, and anovulatory infertility in women [ 9 ]. In addition to these reproductive manifestations, women with PCOS frequently experience a range of comorbidities, including psychological conditions such as anxiety, depression, and body image disturbances [ 10 – 12 ], as well as metabolic complications such as obesity, IR, metabolic syndrome, prediabetes, type 2 diabetes, and cardiovascular risk factors including hypertension and dyslipidemia [ 11 ]. Furthermore, PCOS has been associated with an elevated risk of sleep apnea, endometrial carcinoma, and numerous pregnancy-related complications, such as gestational diabetes, preeclampsia, pregnancy-induced hypertension, postpartum hemorrhage and infections, preterm birth, meconium aspiration, stillbirth, operative deliveries, and shoulder dystocia [ 13 ]. Consequently, PCOS adversely impacts not only reproductive function but also overall health, sexual well-being, and quality of life [ 3 , 14 ]. Currently, the diagnosis of PCOS is based on the Rotterdam criteria, introduced in 2003, which require the presence of at least two out of the following three features: (1) clinical and/or biochemical evidence of hyperandrogenism, (2) ovulatory dysfunction (oligo- or anovulation), and (3) polycystic ovarian morphology, defined as ≥ 12 follicles measuring 2–9 mm in diameter and/or an ovarian volume exceeding 10 mL on ultrasound [ 15 ]. Additionally, PCOS is classified into four phenotypes according to these criteria: phenotype A (ovulatory dysfunction + hyperandrogenism + PCOS), phenotype B (hyperandrogenism + ovulatory dysfunction), phenotype C (PCOS + hyperandrogenism), and phenotype D (ovulatory dysfunction + PCOS) [ 16 ]. Although the precise etiology of PCOS remains uncertain [ 17 ], its pathogenesis is highly complex and multifactorial, encompassing genetic and epigenetic modifications, dietary habits and lifestyle patterns, environmental exposures and transgenerational influences [ 18 , 19 ]. These factors contribute to dysregulation within the hypothalamic-pituitary-ovarian axis, ultimately driving ovarian and adrenal hyperandrogenism [ 20 ]. A key pathophysiological feature of PCOS is hormonal dysregulation, characterized by increased androgen concentrations (hyperandrogenism) and disrupted secretion of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [ 21 ]. An increase in hypothalamic gonadotropin-releasing hormone (GnRH) favors the synthesis of the β subunit of LH over that of FSH, resulting in an increased LH/FSH ratio, which is a hallmark feature of PCOS [ 22 ]. Additionally, elevated LH surges result in follicular arrest at the preantral and antral stages, causing hyperplasia of theca cells and the development of multiple follicles at the periphery of the ovary [ 23 ]. It can be generalized that overactivity of the steroidogenic cascade and LH/FSH surges may trigger ovarian hyperresponsiveness, ultimately leading to hyperandrogenism, disrupted ovarian morphology, and anovulation. Another hallmark of PCOS is IR, which not only aggravates clinical manifestations but also exacerbates hyperandrogenism by increasing circulating free androgen levels [ 24 ].

Despite the promising preclinical evidence summarized in this review, several important limitations must be acknowledged when considering the translational potential of herbal medicines for PCOS. The majority of the available data derive from in vitro experiments and animal models, which, although valuable for mechanistic insight, do not substitute for robust clinical validation in women with PCOS. Well-designed randomized controlled trials with adequate sample sizes remain limited, highlighting a substantial gap between experimental findings and clinical application. Furthermore, significant pharmacological challenges hinder the direct integration of these compounds into clinical practice. Many bioactive phytochemicals demonstrate poor oral bioavailability due to limited solubility, rapid metabolism, and extensive first-pass effects. In addition, variability in plant sources, harvesting conditions, extraction methods, and manufacturing processes leads to inconsistencies in phytochemical composition, complicating standardization and dose determination. Optimal therapeutic dosing regimens for specific PCOS phenotypes have not been clearly established. Potential herb–drug interactions, particularly with commonly prescribed agents such as metformin, oral contraceptives, and ovulation-inducing medications, require systematic investigation. Long-term reproductive safety, especially in women attempting conception, during pregnancy, or lactation, also remains insufficiently characterized. Future research should prioritize rigorously designed randomized controlled trials using standardized extract formulations and clearly defined clinical endpoints in PCOS populations. Mechanistic clinical studies incorporating biomarkers of NLRP3 inflammasome activity would help confirm target engagement in humans and strengthen causal inference. Advanced drug-delivery and formulation strategies may improve the bioavailability of key phytochemicals. In parallel, comprehensive safety profiling, including reproductive toxicity and drug–herb interaction assessments, is essential. Integrative systems pharmacology approaches may further clarify the multi-target nature of herbal medicines and support the development of rational combination therapies.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders and affects an estimated 6–20% of women of reproductive age worldwide [ 1 ]. Characterized by menstrual irregularities, hyperandrogenism, and polycystic ovarian morphology, PCOS significantly impacts women’s reproductive health and overall well-being. Beyond reproductive issues, PCOS is associated with various comorbidities, including insulin resistance (IR), obesity, and mental health disorders. The intricate pathogenesis of PCOS involves multiple factors, including genetic predisposition, hormonal dysregulation, and inflammatory processes [ 2 , 3 ]. Recent research has highlighted the role of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome as a central mediator in the inflammation [ 4 ] and metabolic dysfunction characteristic of PCOS, suggesting that targeting this pathway could provide novel therapeutic avenues [ 5 ]. In this review, we explore the current understanding of PCOS pathophysiology, the involvement of the NLRP3 inflammasome, and the potential of herbal medicines to modulate this inflammatory pathway, thereby offering new insights into effective management strategies.