Beneficial Effects of Fisetin, a Senotherapeutic Compound, in Women's Reproductive Health and Diseases: Evidence from In Vitro to Clinical Studies

The chemical formula of fisetin (3,3′,4′,7-tetrahydroxyflavone) was first described by the Austrian chemist Josef Herzig in 1891 [ 31 ], and its chemical structure was further elucidated by S. Kostanecki in the 1890s. The first chemical synthesis of fisetin was performed in 1904 [ 32 ]. Fisetin is distinguished by four hydroxyl (–OH) groups located at positions 3 and 7 on the A and C rings, and at positions 3′ and 4′ on the B ring ( Figure 1 ). Its chemical structure, particularly the 3′,4′-dihydroxy group, allows it to neutralize reactive oxygen species (ROS) through hydrogen donation [ 32 ]. Fisetin is a widely distributed but relatively low-abundance flavonoid in the plant kingdom. High concentrations are found in fruits, vegetables, nuts, and certain medicinal plants. Among commonly consumed foods, strawberries are considered one of the richest natural sources of fisetin, containing approximately 160 μg/g fresh weight [ 17 ]. Apples, persimmons, grapes, onions, and lotus roots also contain measurable amounts, though typically at lower levels [ 17 ]. Lesser known but significant sources include peaches, kiwis, tomatoes, and cucumbers [ 17 ]. In addition to edible plants, fisetin is present in various traditional medicinal herbs, including Rhus verniciflua [ 33 ]. Fisetin undergoes rapid absorption followed by extensive conjugative metabolism and poor oral bioavailability driven by low solubility and efflux transport ( Figure 2 ). After intravenous administration (30 mg/kg) in rats, fisetin undergoes extensive phase II conjugation, primarily to glucuronides and sulfates, with plasma area under the curve (AUC) ratios of parent–glucuronide–sulfate = 1:6:21 and biliary ratios of 1:4:75, indicating predominant biliary excretion of sulfated metabolites mediated by P-glycoprotein [ 34 ]. An earlier study by Zhang et al. identified 53 in vivo and 14 in vitro metabolites derived from oxidation, reduction, methylation, sulfation, and glucuronidation [ 35 ]. In mice, fisetin is rapidly O-methylated by catechol-O-methyltransferase to form geraldol, its major circulating metabolite. After oral administration (100–200 mg/kg), geraldol showed a higher Cmax and AUC than fisetin, while absolute bioavailability of fisetin remained low (7.8–31.7%), indicating rapid methylation and poor systemic exposure [ 36 ]. Following intraperitoneal administration at 223 mg/kg, plasma fisetin levels reached a peak concentration of 2.5 µg/mL within 15 min and declined in a biphasic manner, with an initial half-life of 0.09 h and a terminal half-life of 3.1 h. Notably, the major metabolite geraldol accumulated at higher concentrations than fisetin itself within Lewis lung tumors [ 37 ]. Formulation strategies have substantially improved fisetin pharmacokinetics. Liposomal fisetin enhanced bioavailability 47-fold and delayed tumor growth compared to free fisetin [ 38 ], while fisetin nanoemulsions achieved 24-fold greater systemic exposure and antitumor efficacy at lower doses [ 39 ]. Nanocochleates further increased relative bioavailability 141-fold and prolonged systemic circulation [ 40 ]. Polymeric and PLGA-based nanoparticles improved dissolution 3-fold and intestinal permeability 4.9-fold [ 41 ], and self-nanoemulsifying systems (SNEDDSs) produced 6–9-fold higher bioavailability with superior neuroprotection [ 42 ]. In healthy human individuals, a fenugreek–galactomannan hydrogel formulation (FF-20) increased fisetin’s AUC 0–12 h 26.9-fold and its Cmax 23-fold, while reducing methylation to geraldol and showing excellent tolerability [ 43 ]. Overall, fisetin exhibits rapid absorption but extensive metabolism and low bioavailability, which can be substantially improved by advanced delivery systems such as liposomes, nanoemulsions, nanocochleates, polymeric nanoparticles, SNEDDSs, and hydrogel formulations. The antioxidant capacity of fisetin starts with the molecule itself, as the 3′,4′-dihydroxy groups on the B ring easily donate hydrogen atoms and act as the main sites that neutralize free radicals [ 44 ]. Using the oxidative stress-sensitive HT-22 neuronal cell model, Ishige et al. reported that fisetin can reduce ROS generation, maintain intracellular glutathione (GSH) levels, and prevent excess Ca 2+ influx during glutamate-induced toxicity, demonstrating multiple protective modes in neurons under oxidative stress [ 45 ]. Fisetin also activated endogenous defense pathways by promoting Nrf2 nuclear translocation and ARE-driven HO-1 expression in human endothelial cells, an effect diminished by PKC-δ or p38 inhibition, which also reduces its protective action against H 2 O 2 -induced injury [ 46 ]. A complementary study with HepG2 cells showed that fisetin can stabilize Nrf2 protein post-transcriptionally by slowing ubiquitin–proteasome-mediated degradation, thereby increasing Nrf2 half-life and upregulating HO-1, GCLC, GCLM, and NQO1 [ 47 ]. Oral fisetin improved pancreatic antioxidant status and lowered lipid peroxidation while normalizing glycemia and inflammatory readouts in streptozotocin-diabetic rats [ 48 ]. After traumatic brain injury in mice, fisetin reduced malondialdehyde (MDA), restored glutathione peroxidase (GPx) activity, decreased neuronal apoptosis, and improved neurological function via Nrf2–ARE activation; notably, Nrf2 deletion abrogated these antioxidant benefits [ 49 ]. In cardiovascular stress models, fisetin lowered myocardial ROS, increased SOD1, CAT, and HO-1, and suppressed pro-hypertrophic MAPK and mTOR signaling [ 19 ]. Fisetin also showed radioprotective antioxidant actions. In γ-irradiated cells, fisetin reduced ROS generation, prevented lipid peroxidation and DNA/protein oxidation, and preserved mitochondrial membrane potential to limit apoptosis [ 50 ]. At the vascular–metabolic interface, fisetin dampens atherogenic pathways by inhibiting Cu 2+ -driven LDL oxidation and reducing macrophage oxLDL uptake through downregulation of PPARγ-dependent CD36 expression [ 51 ]. Importantly, these activities align with broader flavonoid SARs (structure–activity relationships), showing that o-dihydroxyls on ring B and low oxidation potentials track with high ferric-reducing power and radical-trapping capacity [ 44 , 52 , 53 ]. Overall, fisetin acts as a chemically efficient radical scavenger that also amplifies endogenous antioxidant defenses across neuronal, endothelial, hepatic, and cardiac contexts ( Figure 3 ). Extensive evidence from in vitro and in vivo studies demonstrated that fisetin effectively suppresses inflammation across diverse pathological conditions, including metabolic, respiratory, neurodegenerative, cardiovascular, renal, and musculoskeletal diseases ( Figure 3 ). Its anti-inflammatory actions are largely mediated by the suppression of NF-κB, MAPK, PI3K/AKT/mTOR, and TLR4 signaling pathways. In mast cells, fisetin effectively inhibited the activation of MAPK and NF-κB signaling, leading to reduced secretion of inflammatory mediators, including TNF-α, IL-1β, IL-4, IL-6, and IL-8 [ 18 ]. In macrophage and microglial models, fisetin was reported to downregulate iNOS, COX-2, and TNF-α, while inhibiting the nuclear translocation of NF-κB (p65) and phosphorylation of upstream kinases such as Src, Syk, and JNK [ 54 , 55 , 56 ]. Fisetin also suppressed PI3K, AKT, and mTOR phosphorylation, while it promoted autophagosome–lysosome fusion in lipopolysaccharide (LPS)-stimulated macrophages [ 57 ]. Gutiérrez-Venegas et al. [ 58 ] reported that fisetin can inhibit ERK, JNK, and p38 MAPK activation in human gingival fibroblasts, leading to decreased COX-2 expression and PGE 2 release, supporting its anti-inflammatory action in periodontal inflammation. In epithelial tissues, fisetin suppressed cytokine-driven inflammation by attenuating NF-κB p65 nuclear translocation and ERK1/2 phosphorylation, as well as reducing IL-6, IL-8, TNF-α, ICAM-1, and CCL5 expression [ 59 , 60 ]. Similarly, in vascular endothelial cells, fisetin inhibited ROS-NF-κB signaling, CAM expression, and leukocyte adhesion, suggesting vascular protection against hyperglycemia-induced inflammation [ 61 ]. Animal studies further support the strong anti-inflammatory efficacy of fisetin in multiple pathologies. Sahu et al. [ 62 ] showed that fisetin can attenuate DSS-induced colitis by suppressing Akt/p38 MAPK/NF-κB signaling and reducing TNF-α, IL-1β, IL-6, COX-2, and iNOS expression. In allergic asthma and airway inflammation models, fisetin suppressed MyD88 and NF-κB (p65) activation; decreased infiltration of eosinophils and neutrophils; and reduced cytokines, including IL-4, IL-5, IL-13, IL-17, and IL-33 [ 63 , 64 ]. In LPS-induced septic acute kidney injury, fisetin improved renal function by inhibiting Src-mediated NF-κB and MAPK (p38, ERK1/2, and JNK) pathways, as well as suppression of IL-6, IL-1β, TNF-α, COX-2, and HMGB1 expression [ 65 ]. In hepatic ischemia–reperfusion injury, fisetin exerted protection through GSK3β/AMPK activation, which inhibited NLRP3 inflammasome components (caspase-1, IL-1β, and IL-18) and proinflammatory cytokine release [ 66 ]. In degenerative and metabolic diseases, fisetin modulates chronic inflammation via transcriptional and epigenetic mechanisms. Fisetin inhibited NF-κB activation and histone acetylation in hyperglycemia-exposed monocytes, and suppressed IL-6 and TNF-α release and CBP/p300 and histone acetyltransferase activity [ 67 ]. Combined with luteolin, fisetin synergistically reduced NF-κB, ROS, and HAT activity, while it upregulated SIRT1 and FOXO3a [ 68 ]. In osteoarthritis, fisetin also suppressed IL-1β-induced production of TNF-α, IL-6, COX-2, iNOS, MMP-3, MMP-13, and ADAMTS-5 via activation of SIRT1 [ 69 , 70 ]. Clinical and advanced pharmacological studies also support its anti-inflammatory potential. In colorectal cancer patients receiving chemotherapy, 100 mg/day fisetin reduced plasma IL-8, hs-CRP, and MMP-7 levels, indicating systemic anti-inflammatory potential [ 71 ]. Additionally, newly synthesized fisetin derivatives demonstrated stronger inhibition of NF-κB, inflammasome, and ER stress pathways with reduced cytotoxicity [ 72 ]. Overall, these findings strongly support fisetin as a potential anti-inflammatory flavonoid that suppresses key inflammatory mediators such as TNF-α, IL-1β, IL-6, COX-2, iNOS, NF-κB, and MAPK while regulating upstream kinases and epigenetic modulators. Senescence is a cellular state characterized by cell cycle arrest even with a favorable microenvironment [ 73 ]. It is caused by increased activity of cyclin-dependent kinase inhibitors (p16 and p21), leading to resistance to apoptosis and metabolic changes, including accumulation of senescence-associated β-galactosidase (SA-β-gal) [ 73 ]. Senescent cells develop a senescence-associated secretory phenotype (SASP), which involves secretion of proinflammatory cytokines, chemokines, and proteases [ 74 ]. Persistent SASP leads to inflammation, disruption of tissue homeostasis, and local induction of senescence in neighboring cells [ 74 ]. Senescence may be induced by various noxious intracellular or extracellular stimuli, including DNA damage; oncogene activation; telomere dysfunction; and oxidative, metabolic, or mechanical stress [ 23 ]. SASP profiles are highly heterogeneous and depend on cell type; tissue microenvironment; and the nature, intensity, and duration of stress [ 75 ]. Pharmacological strategies targeting senescent cells are broadly referred to as senotherapeutics and can be divided into senolytic and senomorphic agents [ 76 ]. Senolytic drugs selectively eliminate senescent cells. On the other hand, senomorphic drugs modulate SASP and suppress secretory potential without eliminating senescent cells [ 76 ]. This section summarizes evidence supporting fisetin as both a senolytic and senomorphic agent across multiple disease conditions and organ systems. The landmark study by Yousefzadeh et al. [ 77 ] reported the foundational role of fisetin as a natural senolytic agent capable of selectively eliminating senescent cells in aged and progeroid mice. Fisetin treatment reduced senescence markers across multiple tissues, restored tissue homeostasis, and extended both healthspan and lifespan. These findings demonstrated that fisetin treatment could reverse molecular hallmarks of aging through a “hit-and-run” mechanism. Consistent with this, Zhu et al. [ 22 ] reported that fisetin induced apoptosis specifically in senescent human endothelial cells while sparing proliferating cells, indicating its tissue-selective senolytic potential. Mechanistically, fisetin acts through multiple signaling pathways to regulate senescence. Ji et al. [ 78 ] reported that fisetin can ameliorate type 2 diabetes-related vascular aging by targeting the PI3K/Akt/Bcl-2/Bcl-xl axis, promoting apoptosis of senescent endothelial cells, suppressing SASP factors, and enhancing the therapeutic efficacy of metformin, though direct dose equivalence and mechanistic comparisons were not established. Mahoney et al. [ 79 ] extended these findings, showing that fisetin decreased vascular senescence by reducing the viability of senescent endothelial cells while sparing nonsenescent cells. Fisetin also reduced oxidative stress and inflammation in aged mice, improved nitric oxide bioavailability, and reduced arterial stiffness. Beyond vascular systems, fisetin exhibits strong antifibrotic effects. In lupus nephritis, Ijima et al. [ 80 ] revealed that fisetin selectively reduced senescent tubular epithelial cells and myofibroblasts, suppressing TGF-β-driven fibrosis and restoring renal epithelial proliferation. In idiopathic pulmonary fibrosis models, Zhang et al. [ 81 ] demonstrated that fisetin activated AMPK and inhibited NF-κB and TGF-β/Smad3 signaling, reducing alveolar epithelial senescence, collagen deposition, and fibroblast transdifferentiation. Fisetin also exhibits neuroprotective and systemic senolytic actions. Huard et al. [ 82 ] demonstrated that fisetin reduced senescent neurons, astrocytes, and microglia in aged sheep; downregulated senescence and inflammasome genes in peripheral organs; and improved brain and systemic aging markers. Fisetin’s benefits extend to musculoskeletal and degenerative disorders as well. Hambright et al. [ 83 ] demonstrated that fisetin significantly reduced senescent cell burden in murine chondrocytes (ATDC5) and pre-osteoblasts (MC3T3) in vitro, while Zhao et al. [ 84 ] demonstrated reversal of premature aging in telomerase-deficient mice via inhibition of the Stc1/Akt signaling pathway, promoting apoptosis of senescent cells and reduction of p16INK4a/p21CIP1 expression. Furthermore, fisetin exhibits antitumor and adjuvant potential in cancer therapy. Russo et al. [ 85 ] showed that fisetin enhanced the radiosensitivity of resistant cancer cells through AMPK activation and ERK inhibition, promoting autophagy, apoptosis, and attenuation of senescence-associated inflammation. The combination of radiation and fisetin reduced SA-β-gal activity by 40–50% and decreased senescence markers (p16, p21), while inducing both apoptotic and autophagic cell death [ 85 ]. Notably, the translational relevance of fisetin has been validated in higher-order species. Colman et al. [ 86 ] demonstrated that combined dasatinib and fisetin treatment in aged rhesus monkeys significantly reduced epidermal p16 + and p21 + senescent cells without adverse effects, confirming the safety and efficacy of combination senolytic therapy in primates. In addition to senolytic activity, several studies demonstrate fisetin’s ability to suppress SASP. Ji et al. [ 78 ] reported that fisetin can ameliorate type 2 diabetes-related vascular aging by suppressing SASP factors, while Mahoney et al. [ 79 ] showed that fisetin decreased vascular senescence, oxidative stress, and inflammation in aged mice. Fisetin also demonstrated senomorphic activity in fibrotic conditions. In idiopathic pulmonary fibrosis models, Zhang et al. [ 81 ] demonstrated that fisetin activated AMPK and inhibited NF-κB and TGF-β/Smad3 signaling, reducing alveolar epithelial senescence, collagen deposition, and fibroblast transdifferentiation. Similarly, Ashiqueali et al. [ 87 ] reported that fisetin alleviated DSS-induced colitis by downregulating p53, Bcl2, and proinflammatory mediators and restoring beneficial gut microbiota such as Akkermansia muciniphila, indicating senescence- and inflammation-targeted modulation of intestinal homeostasis. In osteoarthritic models, Jacob et al. [ 88 ] found that fisetin and resveratrol reduced senescence in chondrogenic progenitor cells by downregulating p53 and SASP mediators and suppressing inflammation and matrix degradation. Liposomal fisetin formulations, as demonstrated by Henschke et al. [ 89 ], enhanced senomorphic efficacy by reducing IL-6 and IL-8 secretion without inducing cytotoxicity. Kim et al. [ 90 ] found that fisetin delays vascular aging by upregulating PTEN and inhibiting mTORC2-Akt(Ser473) signaling, as well as reduced p53-p21 activation and senescence phenotypes in vascular smooth muscle cells. Similarly, Hambright et al. [ 83 ] reported that fisetin preserved bone density and alleviated frailty-related skeletal degeneration in Zmpste24 − / − progeria mice when administered before advanced pathology developed. Beyond these protective effects, Fang et al. [ 91 ] found that early-life fisetin administration enhanced glucose metabolism, cognitive function, and reduced SASP expression in male mice, indicating sex-dependent responses to preventive interventions. Overall, these studies support fisetin as a broad-spectrum senotherapeutic agent that targets multiple aging pathways and disease conditions from metabolic and cardiovascular dysfunctions to fibrosis, neurodegeneration, inflammation, and cancers ( Figure 3 ). By modulating key molecular targets, including PI3K/Akt, PTEN/mTORC2, AMPK/NF-κB, and TGF-β/Smad3, fisetin effectively clears senescent cells, suppresses SASP, and restores tissue regeneration and homeostasis.

Women are born with a finite number of oocytes stored within primordial follicles. As women age, chromosomal, genetic, mitochondrial, and cytoplasmic factors progressively impair both the quality and quantity of oocytes [ 92 ]. This process, known as ovarian aging, results from the lifelong depletion of the primordial follicle pool and affects all women throughout their reproductive years [ 92 ]. By the mid-30s, the rate of follicle depletion accelerates, contributing to infertility and increased risk of adverse obstetric outcomes [ 93 ]. Ovarian aging is further characterized by heightened oxidative stress, inflammation, mitochondrial dysfunction, and accumulation of senescent cells [ 24 ]. At the molecular level, gene variants in Forkhead Box O3 (FOXO3) and Klotho have been implicated in ovarian aging [ 25 ]. Both genes play key roles in cellular protection by regulating oxidative stress responses and promoting longevity-associated pathways [ 94 ]. Declines in estrogen and progesterone with age also contribute by disrupting menstrual cycle regulation and follicular development [ 94 ]. Current therapeutic approaches for ovarian aging include antioxidant supplementation, stem cell-based therapies, and hormonal or growth factor support [ 95 ]. Since many of these interventions aim to reduce cellular stress, fisetin’s antioxidative and senolytic properties offer potential therapeutic value [ 23 ]. Fisetin reduces oxidative stress through PTEN-mediated inhibition of the pro-oxidant enzyme NADPH oxidase 1 (NOX1), which neutralizes ROS. Its senolytic activity is also significant, as clearance of senescent cells may alleviate inflammation and restore tissue function [ 23 ]. Several animal studies have been conducted to test the potential benefits of fisetin for ovarian aging ( Figure 4 ). In Hyline White laying chickens, Yang et al. [ 96 ] demonstrated that 50 mg/kg/day of fisetin enhanced antioxidant defense, improved egg production, and increased overall egg quality without signs of toxicity. Expression of antioxidant genes, including Gsta, Mgst, Sod, and Gsr, was upregulated, while Western blot analyses showed enhanced glucose metabolism in aged chickens receiving fisetin [ 96 ]. In another study using the same chicken strain, Dong et al. [ 97 ] examined granulosa cell function by treating cells with fisetin at concentrations of 0–80 µM. The activation of the Nrf2/HO-1 pathway and upregulation of the Wnt/β-catenin signaling pathway by fisetin was observed, which was associated with reduced expression of senescence-associated genes such as p53, p21, and p16 [ 97 ]. Using a murine model, Xing et al. [ 98 ] demonstrated that fisetin delays postovulatory oocyte aging through modulation of the Sirt1 pathway, a key regulator of mitochondrial function, apoptosis, and ROS accumulation. In vitro treatment with fisetin (1–20 μM) significantly reduced oxidative stress in aged oocytes and improved mitochondrial function, as evidenced by increased ATP content (0.49 ± 0.014 pmol vs. 0.43 ± 0.014 pmol, p < 0.05) [ 98 ]. However, contrasting findings were reported in reproductive-age mice treated with 5 mg/kg dasatinib plus 50 mg/kg quercetin compared with 100 mg/kg fisetin. While fisetin reduced senescence markers, it did not improve ovarian reserve or fertility outcomes [ 99 ]. Overall, these studies suggest the potential effects of fisetin to modulate pathways involved in ovarian aging, while also highlighting the need for further research. Fertility refers to an individual’s ability to conceive and is regulated in women through a monthly reproductive cycle [ 100 ]. In women, a 5-day fertile window includes the days leading up to ovulation and ovulation day itself, as sperm can reside in the female reproductive tract for many days [ 101 ]. Numerous factors influence fertility, including age, sexually transmitted infections, lifestyle choices, body weight, and environmental exposures [ 102 ]. Among these determinants, oocyte quality is one of the strongest predictors of successful embryo development. Postovulatory oocyte aging, in particular, is associated with reduced fertilization potential and impaired embryonic development [ 98 ]. As described in the previous section, Xing et al. [ 98 ] demonstrated that fisetin protected aging mouse oocytes from oxidative stress and improved mitochondrial function by modulating the Sirt1 pathway. The Sirt1 pathway plays a critical role in reproductive function by protecting gametes from oxidative damage, regulating cellular energy and motility, controlling inflammation, and maintaining proper hormone signaling [ 103 ]. Although Sirt1 activity declines with age, fisetin’s modulation of this pathway was associated with enhanced mitochondrial ATP production and reduced oxidative stress in aged oocytes [ 98 ]. These findings suggest that fisetin might partially compensate for age-related Sirt1 decline through multiple mechanisms which support oocyte health, offering a potential strategy for fertility preservation. In addition to its effects on female gametes, fisetin may benefit male fertility as well. A clinical study conducted in Iran evaluated whether fisetin supplementation could improve sperm integrity during cryopreservation [ 104 ]. In this study, 20 semen samples were divided into three groups: fresh non-frozen control, standard cryopreservation medium, and cryopreservation medium supplemented with 50 μM fisetin. Using sperm DNA fragmentation analysis and multiple chromatin integrity assays, Ezati et al. [ 104 ] found that fisetin significantly improved sperm DNA preservation and motility following cryopreservation. These results highlight the antioxidant capacity of fisetin and suggest that it may enhance assisted reproductive technologies by protecting sperm from cryo-induced oxidative damage. Collectively, the available evidence, though limited, indicates that fisetin may support both female and male fertility by reducing oxidative stress, maintaining mitochondrial function, and preserving gamete integrity ( Figure 4 ). Menopause is a natural transition in a woman’s life marked by the cessation of menses [ 105 ]. Clinically, menopause is defined as the absence of menstrual bleeding or spotting for 12 consecutive months and typically occurs between ages 45 and 55 [ 105 ]. The symptoms of menopause vary widely among individuals and may include weight gain, cognitive impairment, hot flashes, sleep disturbances, vaginal atrophy, decreased libido, and fatigue [ 105 , 106 ]. The loss of estrogen can increase the risk of osteoporosis due to a loss of bone density and raise cholesterol levels, which increase the rate of heart disease and stroke in women [ 107 , 108 ]. As menopause progresses, senescent cells accumulate in multiple tissues, including metabolic organs, bone, and components of the immune system [ 109 ]. These senescent cells secrete SASP factors, which promote inflammation, tissue dysfunction, and systemic decline [ 26 ]. Current therapies for menopausal symptoms primarily involve hormonal treatments aimed at relieving vasomotor symptoms, along with lifestyle-based interventions such as Pilates, which has been shown to improve pain and functional outcomes [ 110 , 111 ]. Given its senolytic and antioxidant properties, fisetin has emerged as a potential therapeutic candidate for reducing menopause-associated dysfunction ( Figure 4 ). Fisetin can eliminate senescent cells that contribute to tissue dysfunction and inflammation and reduce oxidative stress caused by ROS [ 112 ]. Supporting this possibility, Hambright et al. [ 83 ] evaluated the effects of fisetin in murine chondrocyte (ATDC5) and pre-osteoblast (MC3T3) cell lines treated with 50 µM fisetin to investigate its role in bone health. Using Hounsfield unit measurements, bone mineral density assessments, and analyses of specific bone surfaces, they found that fisetin supported bone preservation and might help prevent bone loss, an essential consideration in postmenopausal osteoporosis [ 83 ]. While current evidence suggests that fisetin may alleviate key biological features of menopause, including oxidative stress, inflammation, senescence, and bone degeneration, additional studies are needed to expand this area of research.

Endometriosis is a complex chronic inflammatory condition characterized by the presence of estrogen-dependent endometrial tissue (including both stroma and glands) outside the uterine lining [ 1 ]. It is estimated to affect between 6 and 10% of reproductive-aged females globally [ 113 ]. However, the true prevalence may be higher due to significant diagnostic delays, with an average time between symptom onset and diagnosis of 6.8 years [ 114 ]. Endometriosis commonly leads to chronic pelvic pain, heavy and painful menstrual bleeding (dysmenorrhea), pain during intercourse (dyspareunia), and pain during defecation (dyschezia), and it is a leading cause of infertility [ 115 , 116 ]. The condition is associated with a substantial mental health burden, including increased risk of depressive and anxiety symptoms, and adversely affects health-related quality of life [ 117 ]. Current treatment options include hormonal suppression (estrogen-progestin contraceptives or progestins) and surgical excision of endometriotic lesions or hysterectomy when childbearing is no longer desired. Unfortunately, many patients do not experience relief with these interventions; specifically, up to 34% experience recurrent pelvic pain within 12 months after discontinuation of hormonal medications, and 25% of those who undergo hysterectomy will experience recurrent pelvic pain [ 116 ]. Thus, there is an urgent need to identify novel pharmacological agents that can effectively alleviate symptoms, improve reproductive outcomes, and enhance quality of life for patients with endometriosis. Preclinical evidence suggests that fisetin may offer therapeutic benefit for endometriosis ( Figure 5 and Table 1 ). Arangia and Marino et al. [ 20 ] induced endometriosis in Sprague Dawley rats using intraperitoneal injection of uterine tissue fragments and subsequently treated the animals with fisetin (40 mg/kg). Fisetin significantly altered the morphological, histological, inflammatory, and fibrotic characteristics of endometriotic lesions. Lesions from fisetin-treated rats were visibly smaller; less invasive; and demonstrated significantly reduced diameter, area, and volume [ 20 ]. Histologically, fisetin reduced stromal density and the presence of endometrial-type glands. Fisetin also suppressed inflammation by decreasing mast cell activation, lowering MPO activity, and reducing IL-1β and TNF-α expression [ 20 ]. Antifibrotic effects were evident through reduced collagen deposition on Masson trichrome staining and decreased α-SMA and TGF-β expression. Additionally, fisetin promoted apoptosis, as reflected by increased TUNEL-positive cells, increased Bax and caspase-3 expression, and reduced Bcl-2 levels on Western blots [ 20 ]. Defective decidualization is a central feature of endometriosis-related infertility [ 118 ] and recurrent pregnancy loss [ 119 ]. Single-cell RNA sequencing of menstrual effluent from patients with endometriosis has shown a higher proportion of endometrial stromal cells with proinflammatory and senescent-like phenotypes compared to controls [ 120 ]. Delenko et al. [ 121 ] evaluated the effects of fisetin on primary human endometrial stromal cells isolated from patients at a tertiary care center. Fisetin (25 μM or 50 μM) significantly enhanced decidualization, measured by IGFBP1 protein levels, without inducing cytotoxicity. It also reduced stromal cell migration at 25 μM in wound closure assays and decreased senescent cell burden, as assessed by reduced lipofuscin accumulation [ 121 ]. Mechanistically, fisetin downregulated phosphorylation of AKT, PRAS40, ERK1, and ERK2 [ 121 ], suggesting inhibition of pro-survival and pro-migratory signaling pathways. Overall, these studies indicate that fisetin may target multiple pathological features of endometriosis, including inflammation, fibrosis, senescence, impaired decidualization, and aberrant cellular signaling ( Figure 5 and Table 1 ), and warrant additional studies to determine its efficacy and safety in humans. Effects of fisetin treatment on benign and malignant gynecological diseases. Uterine fibroids, or leiomyomas, are the most common benign tumors of the uterus and are present in up to 70% of reproductive-age women worldwide [ 2 ]. Common risk factors include increasing age, Black race, obesity, hypertension, and vitamin D deficiency [ 130 ]. Histologically, fibroids are monoclonal growths arising from cells in the myometrium (smooth muscle of the uterus). In addition to smooth muscle cells, fibroids contain several populations of immune cells [ 131 ] and fibroblasts that secrete a dense and stiff extracellular matrix [ 27 ]. Morphologically, they vary in size, number, and location, with subtypes including submucosal (abutting the endometrial lining), intramural (situated within the muscular wall of the uterus), and subserosal (developing on the outer surface of the uterus) subtypes [ 132 ]. Clinically, symptoms are present in 25–50% of patients and include heavy, irregular, or prolonged menstrual bleeding, painful periods, pelvic pressure, and abdominal bloating [ 133 ]. Treatment options include medical management, which is often inadequate, leaving patients to seek more invasive yet definitive surgical options such as myomectomy or hysterectomy [ 9 ]. Similarly to endometriosis, there is a pressing need to develop safe and effective treatment options for uterine fibroids. To date, only one study has directly evaluated fisetin as a potential therapeutic for uterine fibroids [ 29 ] ( Figure 5 and Table 1 ). In this study, fisetin decreased the viability of both leiomyoma and myometrial cells in a dose-dependent manner as measured by MTT assay. In leiomyoma cells, there was a statistical decline in viability starting at low concentrations, with decreasing viability at higher concentrations (20, 40, 60, 80, and 100 μM) [ 29 ]. In contrast, myometrial cells showed no significant changes at the lowest fisetin concentration (10 μM), but significance was evident starting at 20 μM and increased in a dose-dependent manner [ 29 ]. Importantly, while both cell types exhibited higher rates of apoptosis when treated with fisetin, leiomyoma cells demonstrated significantly greater fold changes in apoptosis compared to myometrial cells starting at 20 μM [ 29 ]. Mechanistic studies indicated that fisetin activates multiple apoptotic pathways in leiomyoma cells. These include intrinsic and extrinsic apoptosis, MAPK- and p53-mediated signaling, and autophagy-related cell death [ 29 ]. This was evidenced by increased cytochrome C, caspase-8 and caspase-9, and Bax/Bcl-2 expression ratio, as well as activation of p53 and increased microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) expression [ 29 ]. Overall, these findings suggest that fisetin promotes a multifaceted cell death response, with greater sensitivity observed in leiomyoma cells than in normal myometrial cells. Although limited, these early findings highlight the potential of fisetin as a non-hormonal therapeutic strategy for uterine fibroids. PCOS is a chronic, multisystemic syndrome with reproductive, metabolic, endocrine, and inflammatory features [ 134 ]. PCOS is a clinical diagnosis, and the most widely used criteria to diagnose PCOS are the Rotterdam criteria [ 11 ]. These criteria state that two out of three of the following need to be fulfilled for diagnosis: oligo- or anovulation (which typically manifests clinically as irregular or absent periods), clinical and/or biochemical signs of hyperandrogenism (clinical signs typically manifest as hirsutism, while biochemical signs include elevated free testosterone levels), and polycystic appearance of ovaries upon imaging (objectively defined as >12 follicles or ovarian volume >10 mL) [ 11 ]. It is the most common endocrine disorder in women of reproductive age, with a global prevalence of 9.2% [ 135 ]. Aside from the hallmark characteristics of PCOS, it is associated with reproductive and obstetric complications. These include increased rates of infertility, endometrial cancer, preeclampsia, and gestational diabetes [ 3 ]. It also increases the risk of cardiovascular and metabolic complications such as hypertension, dyslipidemia, obesity, and type 2 diabetes mellitus [ 6 ]. Additionally, PCOS is associated with increased rates of mental health conditions such as depression and anxiety [ 7 ]. Treatment of this condition includes a multi-faceted approach of lifestyle interventions managed according to manifesting symptoms. Lifestyle interventions are a mainstay of treatment: dietary changes and physical activity have shown benefit in improving the metabolic health of PCOS patients and decreasing the risk of long-term metabolic and cardiovascular complications [ 136 ]. Pharmacological options include metformin and hormonal birth control pills for menstrual regulation and hirsutism, with the option to add anti-androgens if hirsutism is not controlled [ 137 ]. For anovulatory-related infertility, options include clomiphene citrate or letrozole [ 138 ]. Three preclinical studies have examined the therapeutic potential of fisetin in PCOS, focusing on biochemical, hormonal, histological, inflammatory, and metabolic parameters ( Figure 5 and Table 1 ). In a letrozole-induced PCOS model in Wistar rats, Moustafa et al. [ 122 ] administered fisetin (1.25 mg/kg or 2.5 mg/kg) for 14 days following 21 days of letrozole treatment. Fisetin significantly decreased serum total cholesterol, insulin, glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) compared with untreated PCOS rats. Although these metabolic markers did not fully return to control levels (except serum insulin at 2.5 mg/kg), the improvements were substantial [ 122 ]. Letrozole increased LH and FSH while decreasing AMH; fisetin reversed these abnormalities by reducing LH by 59% and FSH by 50%, and increasing AMH up to 400% at the higher dose [ 122 ]. Histologically, 2.5 mg/kg fisetin restored normal follicular development, improved granulosa cell architecture, and reestablished corpus luteum formation. Fisetin also reduced ovarian IL-1β levels to control values and significantly suppressed NLRP3 inflammasome expression in a dose-dependent manner [ 122 ]. Chahal et al. [ 123 ] induced PCOS in Sprague Dawley rats using mifepristone (20 mg/kg/day for 13 days) and subsequently treated the animals with low-dose (20 mg/kg) or high-dose (40 mg/kg) fisetin. Fisetin significantly reduced fasting glucose, fasting insulin, and HOMA-IR compared with PCOS controls. Hormonal profiles improved markedly, with reductions in testosterone, estradiol, and LH, and increases in progesterone and FSH toward normal values. Fisetin also attenuated inflammation by lowering TNF-α and IL-6 levels, while enhancing antioxidant defense through increased GSH and superoxide dismutase (SOD) [ 123 ]. These findings are consistent with earlier work by Mihanfar et al., who showed that fisetin normalized sex hormone levels (testosterone, estradiol, and progesterone) in letrozole-induced PCOS rats [ 28 ]. Fisetin improved fasting glucose, HOMA-IR, cholesterol, triglycerides, LDL-C, and HDL-C, and boosted antioxidant enzyme activity, including catalase (CAT), SOD, and GPX [ 28 ]. Importantly, fisetin demonstrated efficacy comparable to metformin, a first-line pharmacologic agent in PCOS management [ 28 ], though direct dose equivalence and mechanistic comparisons were not established. Overall, these studies suggest that fisetin exerts broad therapeutic effects in PCOS by improving metabolic dysfunction, restoring hormonal balance, reducing inflammation, enhancing antioxidant capacity, and normalizing ovarian morphology ( Figure 5 and Table 1 ). While promising, these findings are limited to animal studies, and clinical research is needed to determine whether fisetin may serve as a safe, effective, and non-hormonal therapeutic option for women with PCOS.

Ovarian cancer refers to an array of tumors that originate in the ovaries or fallopian tubes. It is associated with significant morbidity and mortality, leading to more deaths than any other gynecological cancer in the United States [ 4 ]. Several risk factors contribute to its development, including genetic predispositions such as germline pathogenic variants in BRCA1/BRCA2 or Lynch syndrome, as well as smoking, endometriosis, infertility, and postmenopausal estrogen replacement therapy [ 139 , 140 ]. The majority of patients (about 80%) are diagnosed at advanced disease stage [ 139 ]. Currently, the mainstay of treatment relies on surgical resection and platinum-based chemotherapy [ 139 ]. Despite these interventions, the five-year relative survival rate between 2015 and 2021 was only 51.6% [ 141 ]. These poor outcomes highlight the need for new therapeutic strategies in light of ovarian cancer’s high heterogeneity and complex cellular origins [ 142 ]. Using the AutoDock Vina system, Abd Ghani et al. [ 143 ] examined the molecular interaction between flavonoids and anti-apoptotic proteins Bcl-2 and Bcl-xl [ 143 ]. Fisetin demonstrated the strongest binding affinity to Bcl-xl (−8.8 kcal/mol) via hydrophobic and electrostatic interactions, and a reasonable affinity to Bcl-2 (−7.1 kcal/mol) through electrostatic interactions with PHE63. These findings suggested that fisetin, like other flavonoids, may function as a pro-apoptotic agent by inhibiting anti-apoptotic proteins in ovarian cancer cells. Liu et al. [ 30 ] further investigated this possibility using ovarian cancer cell lines A2780 and OVCAR-3. Fisetin treatment significantly decreased cell viability in a dose-dependent manner at 25, 50, and 100 μM, as measured by MTT assay [ 30 ]. Annexin V/propidium iodide staining confirmed an increase in apoptosis, and real-time PCR demonstrated reduced mitochondrial cytochrome C mRNA levels [ 30 ], suggesting activation of the intrinsic apoptotic pathway. To assess whether alternative cell death pathways were involved, they used z-VAD, a pan-caspase inhibitor. Although z-VAD partially reduced fisetin-induced apoptosis, it did not restore cell proliferation to levels seen with z-VAD treatment alone [ 30 ], suggesting that additional mechanisms were contributing to cell death. Western blotting revealed increased expression of ZBP1, RIP3, and MLKL in fisetin-treated cells [ 30 ], indicating activation of necroptosis. Necroptosis is a regulated form of cell death implicated in immune clearance and tumor suppression. Dysregulation of necroptosis proteins, particularly MLKL, is associated with cancer progression and poorer survival in ovarian cancer [ 144 , 145 ]. Several studies have also explored its potential as a synergistic agent with platinum-based chemotherapy, which is a mainstay in ovarian cancer treatment along with surgical debulking [ 10 ]. Platinum resistance develops in many patients, especially those with recurrent disease, despite initial responsiveness in approximately 75% of individuals with high-grade serous ovarian carcinoma [ 146 ]. Koren Carmi et al. [ 124 ] demonstrated that co-culturing A2780 cells with murine or human mesenchymal stem cells induced resistance to the platinum prodrug RJY13. Fisetin (10 μM) restored platinum sensitivity by modulating ERK1/2 signaling. While mesenchymal stem cell co-culture reduced phospho-ERK1/2, fisetin treatment upregulated ERK phosphorylation, which reversed drug resistance [ 124 ]. Jafarzadeh et al. [ 125 ] showed that combined use of cisplatin (0.1 μg/mL or 0.5 μg/mL) and fisetin (50 μg/mL or 75 μg/mL or 100 μg/mL) significantly reduced the proportion of viable cells at all possible dose combinations, including when cisplatin was used at a lower concentration than its IC50 of 0.75 μg/mL. Several studies have also explored drug delivery platforms to improve its therapeutic potential. For example, Xiao et al. [ 126 ] used polymeric micelles to encapsulate fisetin and demonstrated enhanced cytotoxicity and apoptosis induction in SKOV3 ovarian cancer cells compared with free fisetin. These results were confirmed in vivo using SKOV3 xenografts in BALB/c athymic nude mice, where encapsulated fisetin produced greater tumor suppression as measured by ultrasound imaging and TUNEL staining [ 126 ]. Overall, these studies suggest that fisetin exerts antitumor effects in ovarian cancer, including induction of apoptosis and necroptosis, inhibition of anti-apoptotic proteins, and reversal of chemotherapy resistance ( Figure 6 and Table 1 ). Drug delivery systems further enhance fisetin’s therapeutic potential in ovarian cancer. Cervical cancer arises from malignant transformation of cells in the cervix, the lower and narrow portion of the uterus. Persistent infection with high-risk human papillomavirus (HPV) genotypes, particularly HPV-16 and HPV-18, accounts for the vast majority of cervical cancer cases globally [ 147 ]. Additional risk factors include smoking, a higher number of sexual partners, and immunosuppressive therapy [ 148 ]. In the United States, significant declines in cervical cancer incidence and mortality over the past two decades reflect successful public health measures such as cervical cancer screening and HPV vaccination programs [ 149 ]. Currently, treatment options include a combination of surgical resection, chemotherapy, and immunotherapy [ 150 ]. The overall five-year relative survival rate is 67% and may reach 91% for early-stage disease [ 151 ]. Fisetin has demonstrated potential anticancer activity in cervical cancer models ( Figure 6 and Table 1 ). Afroze et al. [ 21 ] evaluated fisetin in HeLa cells and observed dose- and time-dependent inhibition of cellular proliferation compared with DMSO-treated controls. Fisetin induced apoptosis through both intrinsic and extrinsic pathways, as evidenced by increased expression of BAX, BAK1, caspase-9, and APAF1, along with decreased BCL-2 in the intrinsic pathway, and upregulation of FAS, FASL, TNF-family ligands, and caspase-8 in the extrinsic pathway [ 21 ]. Fisetin also exerted notable anti-inflammatory effects, reducing expression of cytokines (IL-1 family, IL-4, and IL-11) and chemokines (MCP-1 and MIP-1β) [ 21 ]. At a molecular level, fisetin downregulated key proliferative signaling pathways, including MAPK and PI3K/AKT/mTOR, and activated tumor-suppressive mechanisms through upregulation of ATM, ATF2, VHL, and p53 [ 21 ]. The earlier work by Ying et al. [ 127 ] similarly demonstrated fisetin’s ability to reduce HeLa cell viability in a time- and concentration-dependent manner, with IC50 values of 52 ± 0.9 μM at 24 h and 36 ± 0.5 μM at 48 h. Mechanistically, fisetin induced sustained ERK1/2 phosphorylation, which was associated with fisetin-mediated apoptosis [ 127 ]. In vivo validation using a nude mouse xenograft model revealed significantly reduced tumor growth in mice treated with fisetin compared to controls [ 127 ]. Beyond effects on proliferation and apoptosis, fisetin also exhibits anti-metastatic properties. Chou et al. [ 128 ] found that fisetin (10–40 μM) significantly inhibited motility and invasiveness of SiHa cervical cancer cells, with maximal effects at 20 and 40 μM. Fisetin also suppressed metastasis by inactivating p38 MAPK, blocking NF-κB nuclear translocation, and reducing expression of downstream targets such as urokinase-type plasminogen activator (uPA) [ 128 ]. uPA is known to promote cervical cancer invasion [ 152 ] and may serve as a biomarker for metastatic risk [ 153 ]. Similar to findings in ovarian cancer models, fisetin can act synergistically with targeted therapies. Lin et al. [ 129 ] demonstrated that combining fisetin (40 μM) with sorafenib (2.5 or 5 μM) significantly reduced HeLa cell viability compared with either agent alone. In vivo, HeLa xenografts in nude mice treated with fisetin (4 mg/kg), sorafenib (10 mg/kg), or their combination revealed that dual therapy produced the greatest reduction in tumor volume [ 129 ]. Mechanistically, the combination therapy upregulated death receptor 5 (DR5), enhanced activation of caspase-8 and caspase-3, and increased the Bax/Bcl-2 ratio [ 129 ]. Overall, these findings support the potential anticancer activity of fisetin in cervical cancer, including reduction of proliferation, induction of apoptosis, suppression of inflammation, inhibition of metastasis, and enhanced sensitivity to targeted therapies ( Figure 6 and Table 1 ). Importantly, these findings do not support off-label clinical use of fisetin in gynecologic oncology. No clinical trials have been conducted in these conditions, and human studies are needed to establish safety, optimal dosing, efficacy, and drug interactions.

Clinical trials evaluating fisetin in reproductive health and related diseases remain limited, with only two phase 2 studies ( NCT06113016 and NCT05595499 ) conducted to date in breast cancer survivors ( Table 2 ). The first, a randomized, placebo-controlled interventional trial ( NCT06113016 ), is designed for women who have completed treatment for early-stage (stage I–III) breast cancer and aims to enroll 164 participants. In this study, participants receive fisetin as a nutritional supplement with a structured exercise and supportive-care/quality-of-life program, compared to a control arm receiving placebo plus the same exercise/support program. The trial began on 23 July 2024, with an estimated primary completion date of 30 June 2028 and study completion on 30 December 2028. The main objective is to assess whether the combination of fisetin and exercise can prevent or reduce frailty and functional decline in breast cancer survivors, potentially by eliminating senescent cells and reducing inflammation; secondary aims include improving physical performance, quality of life, and biomarkers of senescence. This trial is now recruiting. A second phase 2, randomized, double-blind, placebo-controlled trial ( NCT05595499 ) is evaluating whether oral fisetin can improve physical function in post-chemotherapy survivors of stage I–III breast cancer. The study consists of two arms—fisetin versus placebo—with no additional drugs administered in combination. Although the ClinicalTrials.gov entry does not report the specific fisetin dose or duration of dosing, the overall study duration spans from baseline assessment to post-treatment functional evaluations. The trial began on 27 March 2023, with an estimated primary and final completion date of 1 June 2026, and aims to enroll 88 participants. The primary objective is to determine whether fisetin improves 6 min walk distance (6MWD) in frail breast cancer survivors, with secondary outcomes including grip strength, Short Physical Performance Battery (SPPB), frailty phenotype, quality-of-life measures, and additional functional or patient-reported outcomes. This trial is also recruiting, and no results have yet been reported. Although clinical trials of fisetin in reproductive health and related diseases are still limited, a significant number of trials have been completed or are ongoing in other health conditions which collectively support its potential efficacy and safety ( Table 2 ). These include mild cognitive impairment ( NCT02741804 ), Gulf War illness ( NCT02909686 ), diabetic and chronic kidney disease ( NCT03325322 ), frail elderly syndrome ( NCT03675724 ), frailty and childhood cancer ( NCT04733534 ), skeletal health ( NCT04313634 ), COVID-19 ( NCT04476953 , NCT04771611 , and NCT04537299 ), knee osteoarthritis ( NCT04210986 , NCT04815902 , NCT05276895 , NCT04770064 , and NCT05482672 ), meniscus tear ( NCT05505747 ), femoroacetabular impingement ( NCT05025956 ), primary open-angle glaucoma ( NCT04784234 ), carpal tunnel syndrome ( NCT05416515 ), multimorbidity ( NCT06431932 ), sepsis ( NCT05758246 ), endothelial dysfunction and arterial stiffness ( NCT06133634 ), and peripheral arterial disease ( NCT06399809 ).

A key limitation is that most in vitro concentrations exceed achievable plasma levels in humans. Across the studies reviewed, in vitro fisetin concentrations ranged from 5 to 300 μM ( Table 1 ), with particularly high doses (up to 300 μM) frequently employed in gynecological cancer models [ 125 , 126 ]. In contrast, fisetin exhibits low oral bioavailability (approximately 7.8–31.7%) due to extensive phase II conjugation and rapid systemic metabolism [ 34 , 36 ]. Pharmacokinetic studies in rodents demonstrate that peak plasma concentrations of fisetin and its major metabolite, geraldol, remain in the low to mid-micromolar range even at high oral doses (up to 200 mg/kg) [ 36 ], indicating a critical pharmacokinetic gap between experimental and physiologically achievable concentrations. In addition, although multiple clinical trials evaluating fisetin are registered or ongoing ( Table 2 ), none is focused on gynecological conditions. As a result, the optimal dosing, long-term safety, and therapeutic efficacy of fisetin in reproductive tissues remain insufficient and require validation in well-designed clinical studies.

Women’s reproductive health disorders, including endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), and gynecologic malignancies, are highly prevalent and contribute substantially to infertility, chronic pain, adverse pregnancy outcomes, and reduced quality of life worldwide [ 1 , 2 , 3 , 4 , 5 ]. In addition to their reproductive consequences, these conditions are frequently accompanied by metabolic, cardiovascular, and mental health comorbidities, underscoring the need for safe and effective long-term therapeutic strategies [ 6 , 7 , 8 ]. Current management heavily depends on hormonal therapies, surgery, and cytotoxic chemotherapy, which may be associated with significant side effects, limited durability of response, and unsuitability for women wishing to preserve fertility [ 9 , 10 , 11 ]. Consequently, there is growing interest in non-hormonal interventions that target shared pathways such as oxidative stress, chronic inflammation, fibrosis, metabolic dysregulation, and cellular senescence [ 12 , 13 , 14 , 15 , 16 ]. Fisetin is a dietary flavonol found in fruits and vegetables such as strawberries, apples, persimmons, and onions [ 17 ]. It exhibits pleiotropic biological activities, including antioxidant, anti-inflammatory, antifibrotic, and antitumor effects [ 18 , 19 , 20 , 21 ]. Importantly, fisetin has been identified as a senolytic agent capable of eliminating senescent cells and attenuating the senescence-associated secretory phenotype (SASP), thereby improving tissue function in preclinical models of aging and chronic disease [ 22 , 23 ]. These mechanisms are highly relevant to reproductive and gynecologic pathophysiology, where oxidative damage, extracellular matrix remodeling, mitochondrial dysfunction, altered immune responses, and cellular senescence may contribute to ovarian aging, subfertility, abnormal uterine bleeding, pelvic pain, and tumor growth [ 24 , 25 , 26 , 27 ]. A growing body of preclinical work suggests that fisetin is capable of modulating key pathogenic processes across multiple reproductive contexts, such as ovarian aging, fertility, menopause, endometriosis, uterine fibroids, PCOS, and gynecologic cancers [ 20 , 21 , 28 , 29 , 30 ]. Parallel early-phase clinical studies in non-gynecologic settings, for example, frailty, metabolic disease, and cancer survivorship, support the feasibility and emerging safety profile of fisetin in humans ( NCT03675724 ; NCT05595499 ; NCT06113016 ). This review explores how fisetin may provide health benefits and reduce symptoms associated with women’s reproductive health, as well as benign and malignant gynecological conditions.

A comprehensive literature search was conducted using PubMed and Google Scholar up to December 2025. For studies related to gynecological diseases, the following search terms were used: “fisetin” AND (“uterine fibroids” OR “leiomyoma” OR “adenomyosis” OR “endometriosis” OR “polycystic ovary syndrome” OR “PCOS” OR “cervical cancer” OR “endometrial cancer” OR “ovarian cancer”). Only full-text articles published in English were included. Peer-reviewed original research articles providing mechanistic, in vitro, in vivo, or clinical evidence of fisetin’s effects in gynecological diseases were eligible for inclusion. Additionally, ClinicalTrials.gov was searched to identify all registered clinical trials involving fisetin across all conditions. Studies were screened initially based on title and abstract, followed by full-text review of potentially relevant articles. For each preclinical study on gynecological diseases, data extracted included gynecological condition studied; study design (in vitro, in vivo); experimental model used; fisetin dosage and treatment regimen; and key findings across multiple features, including antitumor effects (cytotoxicity, proliferation, and apoptosis), histomorphological changes, hormonal and metabolic parameters, inflammatory and oxidative stress markers, anti-metastatic effects, and underlying molecular mechanisms (signaling pathways). For clinical trials, data extracted from ClinicalTrials.gov included trial identifier (NCT number), phase, target conditions, participant demographics (sex and age), enrollment numbers, fisetin dosing regimens, study objectives, study location, and current trial status. As this article is intended as a narrative review, it does not follow a systematic review framework and therefore does not include formal quality assessment or risk-of-bias evaluation of individual studies. In addition, the literature search was restricted to English-language publications, which may have introduced language bias and resulted in the exclusion of relevant studies published in other languages.

Across preclinical models, fisetin emerges as a multifunctional flavonoid with relevance to multiple conditions affecting women’s reproductive health. In ovarian aging and fertility, fisetin attenuates oxidative stress; improves mitochondrial function; modulates Sirt1 and Nrf2/HO-1 signaling; and reduces senescence markers in oocytes, granulosa cells, and ovarian tissue, suggesting potential to preserve gamete quality and delay functional decline. In menopause, its senolytic and antioxidant actions, together with preliminary evidence for bone-protective effects, highlight a possible role in improving skeletal and systemic consequences of estrogen loss. In benign gynecologic disorders such as endometriosis, uterine fibroids, and PCOS, fisetin consistently reduces inflammation, fibrosis, oxidative stress, and senescence, while improving hormonal, metabolic, and histological parameters in animal and cell culture models. In gynecologic malignancies, fisetin induces apoptosis and necroptosis, downregulates survival and proliferative pathways, inhibits migration and invasion, and enhances sensitivity to platinum agents and targeted therapies, particularly in ovarian and cervical cancer models. However, important limitations temper these promising findings. Currently, existing evidence is largely based on in vitro or short-term animal studies. Clinical data are scarce and largely indirect, with no completed randomized trials specifically targeting reproductive or gynecologic indications, except two trials in breast cancer survivors. Pharmacokinetic challenges, including poor solubility, limited bioavailability, and uncertain tissue distribution, remain incompletely addressed, although nanoformulations and micellar delivery systems offer potential solutions. Many studies focus on short-term endpoints, long-term safety, or interactions with standard hormonal therapies, chemotherapeutics, or anticoagulants. In PCOS and benign disease models, comparisons with standard-of-care agents are still sparse. Future research, including rigorous, well-designed trials, is needed. Key priorities include the following: (i) pharmacokinetic and pharmacodynamic studies in humans to define safe and effective dosing strategies, including advanced formulations to overcome hydrophobicity; (ii) early-phase clinical trials in well-defined populations, such as women with PCOS, endometriosis, fibroids, or perimenopausal symptoms, incorporating both symptom-based and biomarker outcomes (senescence, SASP, oxidative stress, and fibrosis); (iii) rigorous evaluation of fisetin as an adjunct to existing therapies, including chemotherapeutic and hormonal regimens, to clarify potential synergy or antagonism. Addressing these gaps will be essential to determine whether fisetin can transition from a promising experimental compound to a clinically useful, non-hormonal adjunct in women’s reproductive and gynecologic health.