Flavonoids represent a major class of plant polyphenols characterized by a C6-C3-C6 skeleton. They are categorized into several classes, including flavones, flavonols, flavanones, isoflavones, flavanols, and anthocyanidins (Stachelska et al., 2025). This classification is based on the oxidation state and substitution pattern of the central heterocyclic C-ring (Hasnat et al., 2024). Luteolin, also known as 3′,4′,5,7-tetrahydroxyflavone, is a representative member of the flavone subclass. Flavones are defined by a C2 = C3 double bond and a carbonyl group at C4 within the C-ring. The presence of four hydroxyl groups at positions 3′and 4′on the B-ring and 5 and 7 on the A-ring underlies luteolin’s potent antioxidant and radical-scavenging properties (Abou Baker, 2022; de Aguiar et al., 2025). These functions are achieved through hydrogen donation and resonance stabilization of phenoxyl radicals (Ibrahim, 2025). The conjugated C2 = C3 bond and 4-oxo group facilitate electron delocalization within the molecule, enhancing luteolin’s affinity for enzymes and receptors through hydrogen bonding and π–π stacking interactions (Abdrabou et al., 2024). Beyond its redox properties, structural and computational studies indicate that luteolin’s planar flavone scaffold allows direct interaction with ATP-binding pockets of key kinases such as PI3K and ERK, and with nuclear receptors including ERα and PPARγ (Lee et al., 2015). These molecular interactions enable luteolin to modulate both metabolic and hormonal signaling, highlighting its importance in oxidative and endocrine regulation.

Luteolin is widely distributed in edible plants, culinary herbs, and beverages, contributing substantially to dietary flavonoid intake. Prominent natural sources include celery (Apium graveolens), parsley (Petroselinum crispum), thyme (Thymus vulgaris), peppermint (Mentha piperita), oregano (Origanum vulgare), green pepper (Capsicum annuum), and rosemary (Rosmarinus officinalis) (Manzoor et al., 2017; Shen et al., 2022). According to the U.S. Department of Agriculture (USDA) Database for the Flavonoid Content of Selected Foods, Release 3.3 (2018), luteolin content typically ranges between 1 and 6 mg/100 g in most herbs and vegetables. Complementary population-based data from the National Health and Nutrition Examination Survey (NHANES) indicate that the median daily intake of luteolin among U.S. adults is approximately 0.3 mg/day (interquartile range: 0.1–0.8 mg/day), with higher consumption noted in Mediterranean and East Asian dietary patterns (Yao and Zhou, 2024). Recent food-science evidence shows that cooking and preparation methods strongly influence flavonoid stability and release. Thermal processes such as boiling or prolonged heating can result in up to 50% reduction in total phenolics, including luteolin, whereas controlled enzymatic or fermentative processing can enhance the aglycone content, thereby improving intestinal absorption and bioavailability (González-Coria et al., 2024). These findings emphasize that food preparation and processing methods play a critical role in determining the effective bioactive exposure to luteolin from dietary sources.

A clear understanding of luteolin’s pharmacokinetic behavior is essential for translating its preclinical promise into therapeutic applications in reproductive disorders. Overall, luteolin displays suboptimal pharmacokinetic performance characterized by limited aqueous solubility, low oral exposure, and rapid systemic clearance (Wang et al., 2024). Its chemical scaffold, particularly the 3′,4′-dihydroxy arrangement and conjugated double bond, enhances antioxidant capacity yet inherently restricts solubility and absorption (Ren et al., 2024). Current evidence further indicates modest systemic availability of the active aglycone and limited tissue penetration, including in reproductive organs. These pharmacokinetic constraints contribute to difficulty achieving in-vivo concentrations comparable to those seen in mechanistic in-vitro studies. As a result, considerable research has shifted toward improving luteolin delivery through nanocarriers, phospholipid complexes, and prodrug approaches designed to enhance solubility, stability, and bioavailability (Ibrahim, 2025).

After oral intake, luteolin is absorbed in the small intestine and undergoes extensive phase II conjugation during first-pass metabolism. These reactions are primarily mediated by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), which generate major circulating metabolites such as luteolin-7-O-glucuronide and luteolin-3′-O-glucuronide (Lv et al., 2025). Consequently, plasma contains predominantly glucuronidated and sulfated conjugates, while the aglycone appears only in trace amounts. These conjugates enter the bile and participate in enterohepatic recycling, which, together with gut microbiota–mediated deconjugation, shapes systemic exposure and contributes to inter-individual variability (Xiong et al., 2023). Double-peak plasma profiles observed in rodents support this recycling phenomenon (Sarawek et al., 2008). Absolute oral bioavailability is generally modest, around 4%–26% depending on formulation and dosing regimen (Wang et al., 2024). This highlights the major influence of solubility and first-pass metabolism on systemic availability. As a result, in-vivo concentrations may fall below thresholds required to reproduce potent mechanistic effects demonstrated in vitro. Figure 1 summarizes luteolin’s structure, dietary origins, and metabolic pathway.

Luteolin’s physicochemical profile is dominated by its extremely low aqueous solubility, with only 0.02–0.03 mg/mL dissolving in water at 27 °C (Rajhard et al., 2021). Despite adequate membrane permeability, this low solubility places luteolin within a Biopharmaceutics Classification System (BCS) class II–type compound, where dissolution (not permeability) is the primary barrier to oral uptake (Chen et al., 2022). Limited dissolution in gastrointestinal fluids restricts the fraction of luteolin that becomes available for absorption, contributing to its low and highly variable oral exposure. These physicochemical constraints provide the rationale for developing formulation strategies specifically aimed at enhancing solubility and dissolution to improve systemic availability.

Polycystic ovary syndrome is a common endocrine and metabolic disorder affecting 8%–13% of women of reproductive age. It is characterized by chronic anovulation, hyperandrogenism, insulin resistance, and ovarian morphological changes (Almhmoud et al., 2024). The pathogenesis of PCOS is linked to oxidative stress, inflammation, and alterations in steroid hormone production (Rosenfield and Ehrmann, 2016). Given its multifactorial nature, therapeutics that simultaneously target oxidative stress, inflammation, steroidogenic imbalance, and insulin resistance are of growing interest. Luteolin’s broad antioxidant, anti-inflammatory, and metabolic regulatory actions make it a strong candidate for modulating several key pathways implicated in PCOS pathophysiology.

In the widely used letrozole + high-fat diet rat model, luteolin administration significantly improved reproductive and metabolic features (Huang and Zhang, 2021). Luteolin restored estrous cyclicity, improved follicular maturation, and normalized hormone profiles (↓LH, ↓testosterone, ↑FSH, ↑estradiol). Metabolically, it reduced hyperinsulinemia and improved insulin sensitivity (↓HOMA-IR), accompanied by enhanced ovarian antioxidant defenses. These findings suggest that luteolin supports ovarian function in PCOS by improving both endocrine balance and metabolic responsiveness, likely through modulation of insulin signaling and oxidative status within the ovary.

Building on these findings, Dai et al. (2025) extended the therapeutic relevance of luteolin to PCOS complicated by obesity, a phenotype that amplifies metabolic stress and worsens reproductive outcomes. In an obese rat model of PCOS, luteolin markedly improved estrous cyclicity, restored ovarian morphology, enhanced glucose tolerance, and reduced dyslipidemia (↓TG, ↓TC, ↓LDL-c). Beyond reproductive improvements, luteolin showed strong metabolic benefits by attenuating hepatic steatosis and reversing the expression of key liver genes involved in mitochondrial function, insulin signaling, and lipid metabolism (including UQCRC2, IRS2, NFIX, and ALDH6A1). Metagenomic profiling further demonstrated that luteolin increased gut microbial diversity and shifted the microbiota toward a healthier composition, notably increasing Bacteroidota and decreasing Firmicutes. These findings highlight luteolin’s multi-system role in PCOS, demonstrating that its benefits extend beyond ovarian function to include hepatic metabolic regulation and restoration of gut microbiota homeostasis—processes highly relevant in obesity-exacerbated PCOS.

Beyond endocrine-metabolic PCOS models, luteolin also mitigates environmentally induced PCOS-like ovarian dysfunction. Bisphenol A (BPA), a well-established endocrine disruptor, induces ovarian injury through oxidative stress, mitochondrial dysfunction, and dysregulation of PCOS-associated genes (Urbanetz et al., 2023). In Chinese Hamster Ovary (CHO) cells, luteolin reduced reactive oxygen species (ROS) accumulation, prevented mitochondrial depolarization, and suppressed apoptosis (Sudhakaran et al., 2024). In zebrafish models, luteolin normalized follicular maturation, increased superoxide dismutase (SOD) activity, improved gonadosomatic index, and decreased follicular atresia. It also downregulated inflammatory and PCOS-associated genes (TNF-α, IL-1β, TOX3, DENND1A) and improved acetylcholinesterase activity (Sudhakaran et al., 2024).

Primary ovarian insufficiency (POI), historically referred to as premature ovarian failure (POF), affects 1%–3% of women under 40 and arises from accelerated follicular loss or dysfunction (Touraine et al., 2024). Causes include oxidative stress, apoptosis, cytotoxic chemotherapeutic agents, autoimmune injury, and DNA damage (Wu J. et al., 2025). In cyclophosphamide-induced POI, luteolin improved serum levels of estradiol, progesterone, AMH, LH, and FSH, restoring endocrine function (Pan et al., 2025). Histologically, luteolin preserved follicular architecture, reduced granulosa cell apoptosis, and increased antioxidant enzyme activity. Markers of oxidative injury and DNA damage (MDA, 4-HNE, 8-OHdG) were significantly reduced. High-level mechanistic evidence suggests luteolin supports DNA repair processes, reduces oxidative injury, and maintains granulosa cell viability, factors essential for ovarian reserve preservation.

Endometriosis is a chronic, estrogen-dependent inflammatory disorder characterized by the ectopic implantation and growth of endometrial tissue. It affects 10%–15% of reproductive-aged women and up to half of infertile women (Tsamantioti and Mahdy, 2025). The disorder is sustained by a complex interplay of hormonal responsiveness, persistent inflammation, aberrant immune-lesion communication, angiogenesis, and progressive fibrotic remodeling (As-Sanie et al., 2025). These processes collectively promote the survival, invasion, and vascularization of ectopic lesions. Luteolin has demonstrated multifaceted therapeutic actions across both in vitro and in vivo models of endometriosis. In human 12Z endometriotic epithelial cells, luteolin suppresses proliferation and induces apoptosis through activation of caspase-dependent pathways (Woo et al., 2021). Beyond its direct cytotoxic effects on ectopic epithelial cells, luteolin disrupts key immune-lesion interactions that support disease progression. It significantly reduces the expression of chemokines such as CCL2 and CCL5, thereby limiting the recruitment of pro-endometriotic macrophages. In macrophage co-culture systems, luteolin inhibits M2-like polarization, a macrophage phenotype known to promote angiogenesis, fibrosis, and lesion maintenance. Consistent with these immune-modulatory actions, luteolin downregulates VEGF and matrix metalloproteinases (MMP-2 and MMP-9), attenuating neovascularization and extracellular matrix remodeling (Woo et al., 2021).

Complementary evidence from Park et al. (2019) demonstrates that luteolin targets fundamental proliferative and survival pathways within endometriotic cells. Using human endometrial/ectopic cell lines (VK2/E6E7 and End1/E6E7) and a mouse auto-implantation model, the study showed that luteolin markedly reduces lesion growth in vivo. Mechanistically, luteolin induces G0/G1 cell-cycle arrest through downregulation of critical cell-cycle regulators, including CCNE1, CDK2, and CDK4. It simultaneously inhibits PI3K/Akt and MAPK signaling—core pathways that support cell survival, proliferation, and resistance to apoptosis in endometriotic tissue. This coordinated suppression of proliferative and pro-survival networks leads to increased apoptosis and significant reduction in implant size in vivo.

Endometritis is a bacterial inflammation of the endometrial lining affecting 2%–5% of women following childbirth or uterine instrumentation. It contributes to infertility, pelvic pain, and impaired implantation (Yan et al., 2025). Disease progression involves microbial invasion, excessive cytokine production, disruption of epithelial barrier proteins, oxidative stress, and in severe cases, ferroptotic injury to endometrial tissue (Tabeeva et al., 2024). Emerging evidence demonstrates that luteolin exerts broad protective actions across multiple experimental models of infectious endometritis. In a Staphylococcus aureus–induced mouse model, luteolin markedly attenuated uterine inflammation, reducing neutrophil infiltration, edema, and tissue injury (Gao et al., 2024). Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) were significantly suppressed, while epithelial barrier integrity was restored through upregulation of tight-junction proteins ZO-1 and occludin. Luteolin also inhibited ferroptosis by lowering malondialdehyde (MDA) and ferrous iron (Fe²⁺), while increasing glutathione and GPX4 levels, highlighting its ability to mitigate oxidative epithelial damage.

Complementary findings from an LPS-induced endometritis model further support luteolin’s anti-inflammatory and antioxidant potential (Shaukat et al., 2024). Therapeutic administration of luteolin substantially reduced uterine histopathological injury and suppressed pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), while increasing the anti-inflammatory cytokine IL-10. Luteolin enhanced antioxidant defenses (↑SOD1, ↑CAT, ↑GPx1; ↓MDA, ↓ROS) and modulated innate immune signaling by upregulating TLR4 expression yet simultaneously inhibiting NF-κB activation. Activation of Nrf2 further contributed to oxidative stress resolution. Collectively, these data indicate that luteolin counteracts LPS-triggered endometrial injury through coordinated modulation of TLR4-associated Nrf2 and NF-κB pathways. Luteolin also demonstrates therapeutic activity against biofilm-associated endometritis, which is typically more resistant to antimicrobial therapy (Zhang et al., 2022). In T. pyogenes, a major opportunistic pathogen causing suppurative uterine infections, luteolin dispersed mature biofilms and significantly inhibited the expression of biofilm-related genes (luxS, plo, rbsB, lsrB). In a rat endometritis model induced by glacial acetic acid followed by Trueperella pyogenes inoculation, luteolin treatment reduced uterine inflammation and symptom severity, highlighting its potential role in managing refractory biofilm-associated infections.

Uterine leiomyomas (fibroids) are the most common benign gynecologic tumors, affecting 20%–40% of reproductive-aged women and up to 70% by age 50 (Bulun et al., 2025). Their growth is driven by estrogen and progesterone signaling, chronic oxidative stress, inflammation, and excessive ECM accumulation, which together promote smooth muscle cell proliferation, fibrosis, and tumor persistence (Fartushok et al., 2025). Evidence indicates that luteolin exerts both anti-fibrotic and anti-proliferative effects in leiomyoma models. In a diethylstilbestrol (DES) + progesterone rat model, luteolin significantly reduced uterine enlargement, collagen deposition, and myometrial architectural distortion (Binmahfouz et al., 2025). These structural improvements were accompanied by restoration of antioxidant enzyme activity and suppression of lipid peroxidation (↓MDA), as well as normalization of apoptotic regulators, including an improved Bax/Bcl-2 ratio. Luteolin also attenuated pro-inflammatory mediators such as IL-6, TNF-α, and NF-κB and reduced myofibroblast activation (α-SMA), consistent with inhibition of fibrotic remodeling and restoration of redox homeostasis.

Complementary in vitro evidence highlights luteolin’s direct effects on leiomyoma smooth muscle cells. In studies using Scutellaria barbata extracts, five flavonoids, including luteolin, were isolated and evaluated for bioactivity. Among these, luteolin (alongside apigenin) demonstrated marked anti-proliferative activity in human leiomyoma smooth muscle cells while also inducing apoptosis (Kim et al., 2005). Mechanistically, luteolin reduced the expression of insulin-like growth factor-I (IGF-I) at both mRNA and protein levels. Because IGF-I is overexpressed in leiomyoma cells and drives selective tumor growth compared with normal myometrium, its downregulation represents a key pathway through which luteolin suppresses leiomyoma expansion. These findings support luteolin as a selective inhibitor of leiomyoma cell growth that acts through apoptosis activation and growth factor modulation.

Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by new-onset hypertension, proteinuria, and multi-organ dysfunction after 20 weeks of gestation (Martini et al., 2025). It remains a leading cause of maternal and perinatal morbidity and mortality worldwide. A central driver of PE is placental ischemia and hypoxia, which stimulate aberrant production of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), pro-inflammatory cytokines, and oxidative stress mediators (Jena et al., 2020). These signals converge on maternal endothelial dysfunction and excessive endothelin-1 (ET-1) production, driving vasoconstriction and hypertension. Given the safety limitations of pharmacologic antihypertensives during pregnancy, the exploration of nutraceuticals with anti-inflammatory and antioxidant properties has attracted increasing interest (Hup et al., 2025).

Recent studies have identified luteolin as a promising candidate capable of targeting multiple pathogenic pathways in PE. In cultured human placental cytotrophoblasts and explants from normotensive and preeclamptic pregnancies, luteolin was identified as a potent inhibitor of sFlt-1 release, reducing secretion by more than 95% compared to vehicle controls (Eddy et al., 2023). This effect occurred in a dose- and time-dependent manner and was associated with marked suppression of HIF-1α, a transcription factor upregulated in hypoxic placentae and a principal driver of sFlt-1 expression. Mechanistic experiments demonstrated that inhibition of PI3K/Akt signaling recapitulated luteolin’s effects on HIF-1α, suggesting that luteolin downregulates sFlt-1 at least in part through PI3K/Akt-dependent inhibition of HIF-1α stabilization. Follow-up studies further showed that luteolin mitigates inflammatory and oxidative stress pathways central to PE pathophysiology (Eddy et al., 2024). In human placental explants and endothelial cells stimulated with TNF-α, a cytokine elevated in PE, luteolin significantly reduced NF-κB activation, ROS, and superoxide production. Luteolin also decreased TNF-α-induced secretion of IL-6 and endothelin-1 (ET-1), the latter being a potent vasoconstrictor linked to maternal hypertension in PE. Collectively, these findings demonstrate that luteolin interrupts both inflammatory and vasoactive signaling cascades, restoring endothelial homeostasis.

Gynecologic cancers, including ovarian, cervical, and endometrial cancers, account for around 20% of global female cancer burden (Bray et al., 2024). Despite therapeutic advances, challenges such as chemoresistance, survival of tumor stem-like cells, and metastatic spread persist. Luteolin has shown promising preclinical effects targeting several of these pathways. Cancer stem cells promote recurrence and therapeutic resistance. Luteolin directly binds KDM4C, a histone demethylase, leading to reduced stemness and tumor progression (Li et al., 2023). In CD133⁺/ALDH⁺ stem-like ovarian cancer cells, luteolin decreased sphere formation and downregulated stemness genes (SOX2, OCT4, NANOG). It also increased sensitivity to paclitaxel and carboplatin. In xenografts, luteolin (100 mg/kg IV) reduced tumor burden and prolonged survival without systemic toxicity, supporting its potential as a safe adjunct targeting tumor stemness (Li et al., 2023).

In Ca Ski cervical cancer cells, luteolin (25–100 µM) inhibited proliferation and induced intrinsic apoptosis characterized by caspase activation and mitochondrial dysfunction (Pei et al., 2024). Synergistic cytotoxic activity was observed when luteolin was combined with asiatic acid, with enhanced apoptotic effects and suppression of AKT/mTOR/NF-κB signaling (Chen et al., 2023). These data suggest luteolin as both a standalone and combination adjunct for cervical cancer therapy.

Transcriptomic analyses indicate that luteolin targets genes involved in IL-17 signaling, oxidative stress regulation, and homologous recombination repair (Zhao et al., 2023). In AN3-CA endometrial carcinoma cells, luteolin (5–15 µM) reduced migration and expression of MMP1, IL-17, and VEGF, key mediators of angiogenesis and metastasis. This supports luteolin’s potential role in modulating inflammatory and angiogenic pathways in endometrial malignancy. Collectively, the disease-specific findings summarized above are consolidated in Table 1, which outlines the key experimental models, doses, mechanisms, and outcomes across reproductive disorders.

Follicular development and oocyte quality depend on the integrity of the granulosa-oocyte unit, which is highly sensitive to oxidative stress, mitochondrial dysfunction, and apoptotic signaling (Wu D. et al., 2025). Beyond disease-specific outcomes, accumulating evidence indicates that luteolin modulates core mechanisms governing folliculogenesis and follicular survival. Across experimental models, luteolin consistently limits oxidative injury within granulosa cells, preserves mitochondrial function, and suppresses apoptosis, thereby reducing follicular atresia and supporting orderly follicular progression.

Mechanistically, luteolin activates antioxidant defense pathways, particularly Nrf2-regulated enzymes, while modulating PI3K/AKT signaling involved in granulosa cell survival and metabolic support of the oocyte (Ghantabpour et al., 2025). In chemotherapy- and toxin-induced ovarian injury models, luteolin preserves primordial and growing follicles, reduces granulosa cell apoptosis, and maintains circulating AMH levels, indicating stabilization of the functional ovarian reserve (Pan et al., 2025). Complementary evidence from environmental ovotoxicity models demonstrates that luteolin attenuates mitochondrial depolarization, restores follicular architecture, and improves follicular maturation, effects that are directly relevant to oocyte competence (Sudhakaran et al., 2024). Collectively, these findings support a fertility-centered role for luteolin as a modulator of follicular integrity and oocyte-supportive microenvironments, providing a mechanistic bridge between molecular signaling and reproductive potential.

Oxidative stress is a common driver of tissue dysfunction across reproductive disorders. It contributes to disrupted folliculogenesis in PCOS, epithelial injury in endometritis, and fibrotic remodeling in leiomyomas (Kumar and Ramanarayanan, 2025; Oyovwi et al., 2025). Luteolin restores redox homeostasis through both direct chemical antioxidant activity and activation of endogenous defense pathways. Structurally, its ortho-dihydroxy (catechol) configuration confers a strong electron-donating capacity, enabling neutralization of ROS via hydrogen-atom transfer and single-electron transfer mechanisms, while its planar conjugated system stabilizes radical intermediates (de Aguiar et al., 2025). Luteolin also chelates transition metals such as Fe²⁺ and Cu²⁺, thereby reducing Fenton-type ROS production (Ghozzi et al., 2024). Complementing these direct effects, luteolin activates the Nrf2/ARE antioxidant pathway by promoting dissociation of Nrf2 from Keap1, facilitating its nuclear translocation and induction of antioxidant genes including HO-1, NQO1, SOD, and CAT (Thiruvengadam et al., 2021). Upstream signaling through PI3K/AKT, MAPK (ERK/JNK/p38), and PKC further enhances Nrf2 stabilization and transcriptional activity. Together, these mechanisms underlie luteolin’s capacity to mitigate oxidative injury across multiple tissues: improving ovarian redox balance in PCOS (Huang and Zhang, 2021; Ghantabpour et al., 2025), preventing lipid peroxidation and ferroptosis in endometritis (Khan et al., 2024), and reducing oxidative fibrosis signaling in leiomyomas (Binmahfouz et al., 2025). By enhancing redox homeostasis, luteolin protects cellular structures, supports hormone synthesis, preserves epithelial integrity, and stabilizes mitochondrial function.

Inflammation is a key pathogenic driver across reproductive disorders, promoting ovulatory dysfunction in PCOS, lesion survival in endometriosis, leukocyte infiltration in endometritis, and tumor progression in malignancies. Luteolin exerts multi-level suppression of inflammatory signaling by targeting several interconnected cascades. NF-κB is a central regulator of inflammatory gene expression (Singh et al., 2024). Luteolin suppresses this pathway by preventing phosphorylation and degradation of the inhibitory protein IκBα, thereby blocking nuclear translocation of NF-κB p65 and reducing transcription of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), iNOS, COX-2, and adhesion molecules (Khan et al., 2024). In parallel, luteolin interferes with MAPK signaling by reducing activation of ERK, JNK, and p38 kinases, key upstream amplifiers of cytokine and chemokine production (Almatroodi et al., 2024). Together, the dual inhibition of NF-κB and MAPK pathways attenuates inflammatory cascades, decreases immune cell recruitment, and disrupts the feed-forward loop sustaining chronic inflammation in reproductive tissues.

Chemokines such as CCL2 and CCL5 play essential roles in immune cell recruitment and polarization within reproductive tissues, and their dysregulation promotes chronic inflammation, macrophage infiltration, angiogenesis, and fibrotic remodeling characteristic of endometriosis and related disorders (Li et al., 2022; Guo et al., 2025). In endometriosis models, luteolin suppresses the expression of macrophage-recruiting chemokines (CCL2, CCL5) and reduces alternative (M2) macrophage polarization, thereby disrupting the macrophage-driven inflammatory and fibrotic microenvironment that supports lesion persistence (Woo et al., 2021). M2 macrophages are known to promote tissue repair, ECM deposition, angiogenesis, and lesion maintenance, and their inhibition reduces the inflammation that sustains disease progression (Guan et al., 2025; Wang et al., 2025). Such modulation alleviates the chronic inflammatory state underlying endometrial and ovarian pathologies (Zdrojkowski et al., 2023). Overall, these anti-inflammatory effects help disrupt the pathological feedback loops linking inflammation with oxidative stress, fibrosis, and hormonal imbalance.

Fibrosis is a major driver of structural distortion and functional impairment across multiple reproductive disorders, most notably uterine leiomyomas and chronic endometriosis (Vissers et al., 2024). Luteolin exerts potent anti-fibrotic activity by targeting the transforming growth factor-β (TGF-β) axis and re-establishing balanced apoptotic signaling (Wang et al., 2024). By suppressing TGF-β1 expression and preventing Smad2/3 phosphorylation, luteolin downregulates core ECM components, such as collagen I, fibronectin, and alpha-smooth muscle actin (α-SMA), thereby limiting myofibroblast activation and pathological ECM accumulation. In parallel, luteolin enhances apoptosis in aberrantly proliferative tissues through activation of caspase-3, -8, and -9, disruption of mitochondrial membrane potential, and induction of DNA fragmentation (Pei et al., 2024). Together, these anti-fibrotic and pro-apoptotic mechanisms contribute to reduced fibroid burden and ECM deposition in leiomyomas, diminished lesion density and invasiveness in endometriosis, and improved tissue homeostasis in fibrosis-associated gynecologic malignancies.

The PI3K/AKT/PTEN axis integrates metabolic control, cell survival, and growth factor responses in reproductive tissues (Matsuda et al., 2013). Dysregulation contributes to insulin resistance in PCOS, fibrotic proliferation in leiomyomas, and survival of cancer stem cells (Makker et al., 2011). Luteolin modulates PI3K/AKT signaling in a context-dependent manner, enhancing insulin-related signaling in PCOS models, while inhibiting pathological PI3K/AKT activation in fibrotic or malignant tissues (Li et al., 2016). Luteolin upregulates PTEN in leiomyoma models, counteracting PI3K-driven proliferation (Binmahfouz et al., 2025). This context-dependent modulation is beneficial, promoting cell survival in metabolic disorders (PCOS) while suppressing pathological proliferation in fibrotic conditions. Many gynecologic tumors exhibit aberrant PI3K/AKT activity (Rascio et al., 2021). Luteolin’s ability to suppress PI3K signaling while stabilizing PTEN may contribute to its antiproliferative and chemosensitizing effects in cancer models. Overall, luteolin helps restore metabolic signaling in PCOS, suppresses proliferative signaling in leiomyomas, and modulates survival pathways in cancer.

Hormonal balance depends on coordinated estrogen and progesterone signaling. Disturbances, such as estrogen dominance or progesterone resistance, drive the progression of endometriosis, PCOS, and leiomyomas (Valiyevna, 2025). Molecular docking and biochemical studies indicate that luteolin interacts with estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β) within their ligand-binding domains (D’Arrigo et al., 2021). This interaction produces hormone-context–dependent behavior, enabling luteolin to support estrogen-responsive gene expression in low-estrogen states while competitively limiting estrogen-driven proliferationin estrogen-dominant states. By modulating ER and PR pathways in this bidirectional manner, luteolin may correct hormonal imbalances that perpetuate reproductive pathology.

At the receptor level, luteolin’s differential binding to ER-α and ER-β allows it to function as a weak phytoestrogenic selective estrogen receptor modulator (SERM), displaying partial agonist activity in estrogen-deficient environments and antagonistic effects under estrogen-excess conditions (Maximov et al., 2013). Through this selective receptor modulation, luteolin restrains pathological estrogenic stimulation while preserving physiological endocrine signaling and endometrial differentiation, supporting its potential therapeutic value in hormone-dependent reproductive disorders.

The pathways described above operate as an integrated signaling network rather than isolated linear cascades. Crosstalk between oxidative stress and inflammatory nodes is central to this network: PI3K/AKT can promote Nrf2 activation and antioxidant gene expression, while activated Nrf2 dampens NF-κB–driven transcription and limits ROS-mediated injury (Gao et al., 2022; Khassafi et al., 2024). In turn, persistent NF-κB activation upregulates TGF-β signaling, linking chronic inflammation to fibroblast activation and extracellular matrix deposition (Guo et al., 2024; Sheikh et al., 2025). TGF-β feeds back on PI3K/AKT/PTEN, shifting signaling from cytostatic responses toward pro-survival and pro-fibrotic programs in a context-dependent manner (Zhang et al., 2013). Estrogen and progesterone receptors further intersect with these nodes through rapid non-genomic activation of PI3K/AKT and MAPK cascades, thereby coupling steroid hormone status to cell survival and proliferation in reproductive tissues (Moriarty et al., 2006; Khatpe et al., 2021). By acting at these convergent signaling pathways, luteolin disrupts maladaptive redox–inflammatory–fibrotic–endocrine feedback loops and helps re-establish homeostasis in reproductive tissues, providing a systems-level explanation for its reproducible benefits across diverse gynecological disorders (Figure 2).

These supplements are primarily available in capsule, tablet, or powder form, with typical dose ranges from 50 mg to 800 mg. They are marketed for general wellness benefits, including antioxidant properties, immune system support, and neuroprotective potential.

Luteolin is often included in multiple-ingredient formulations that contain other bioactive compounds, such as flavonoids, fatty acids, or vitamins. These combination products are generally promoted for their antioxidant, anti-inflammatory, or neuroprotective properties, rather than for gynecological or endocrine-related indications.

Luteolin’s therapeutic potential is further constrained by fundamental biopharmaceutical limitations, including poor aqueous solubility, low membrane permeability, and extensive phase II metabolism, all of which restrict its oral bioavailability (Hasnat et al., 2024; Wang et al., 2024). Accordingly, formulation research has expanded from basic solubility enhancers to advanced delivery systems such as nanoemulsions, liposomes, polymeric nanoparticles, and metal–organic frameworks (Alshehri et al., 2020; Batool et al., 2020; Liu et al., 2021; Miao et al., 2021; Wu et al., 2024). However, these formulation advances have not been translated into reproductive-disorder research. In PCOS, endometriosis, and hormone-induced leiomyoma models, luteolin is almost exclusively administered in its unmodified form, typically as a simple intraperitoneal solution or oral suspension, without strategies to improve stability, absorption, or targeted delivery (Park et al., 2019; Huang and Zhang, 2021; Binmahfouz et al., 2025; Dai et al., 2025). Advanced systems, such as nano-encapsulated carriers or ligand-targeted formulations, have only been explored in gynecologic malignancies and almost entirely at the in vitro level, exemplified by luteolin-loaded ZIF-8 metal–organic frameworks and folate-functionalized mesoporous silica nanoparticles used in cervical cancer models (Li et al., 2022; Chen et al., 2023). This divergence underscores a clear translational gap. Although luteolin demonstrates promising biological effects across multiple reproductive pathologies, these findings rely on suboptimal pharmacokinetic conditions and non-targeted distribution. Future research incorporating optimized delivery platforms, including nanoemulsions, phytophospholipid complexes, polymeric nanoparticles, or uterus-targeted systems may substantially enhance luteolin’s therapeutic performance in reproductive medicine.