Systems-level actions of luteolin in female reproductive disorders: from molecular mechanisms to clinical translation

Female reproductive health is influenced by a complex interplay of endocrine, metabolic, inflammatory, and tissue-remodeling processes. Disruptions in these systems can lead to a range of chronic gynecological conditions that affect millions of women worldwide ( Sharami et al., 2025 ). These disorders include polycystic ovary syndrome (PCOS), endometriosis, uterine leiomyomas, primary ovarian insufficiency (POI), endometritis, and gynecologic cancers. Despite their clinical heterogeneity, these disorders share convergent pathological drivers, including oxidative stress, chronic inflammation, hormonal dysregulation, metabolic dysfunction, aberrant extracellular matrix (ECM) remodeling, and impaired apoptosis ( As-Sanie et al., 2025 ; Fartushok et al., 2025 ; Kumar and Ramanarayanan, 2025 ). Current medical and surgical treatments primarily address symptoms but do not effectively target the mechanisms central to disease progression and recurrence ( Azam et al., 2025 ). As a result, there is a significant need for multi-target interventions that can simultaneously restore balance across redox, immune, endocrine, and metabolic systems. Luteolin, a naturally occurring flavone found in various herbs, vegetables, and botanical preparations, has emerged as a promising candidate for integrated therapeutic modulation ( Zhu et al., 2024 ). Its chemical structure, characterized by a planar 3′,4′,5,7-tetrahydroxyflavone scaffold, confers strong antioxidant, anti-inflammatory, anti-fibrotic, and metabolic-regulatory properties ( Hasnat et al., 2024 ; Ibrahim, 2025 ). Mechanistically, luteolin engages multiple molecular networks, including the Nrf2/ARE antioxidant axis, NF-κB/MAPK inflammatory cascades, PI3K/AKT/PTEN metabolic-survival pathway, TGF-β/Smad fibrotic signaling, and estrogen (ER) and progesterone (PR) receptor-mediated hormonal regulation ( Thiruvengadam et al., 2021 ; Khan et al., 2024 ). This broad mechanistic spectrum provides a compelling rationale for luteolin’s consistent benefits across diverse reproductive disorders. Extensive preclinical evidence supports these mechanistic insights, demonstrating that luteolin restores key cellular and endocrine functions across reproductive models. In PCOS, it enhances insulin sensitivity, normalizes ovulatory function, and reduces ovarian oxidative damage ( Dutta et al., 2025 ; Yuan et al., 2025 ). For endometriosis, luteolin disrupts macrophage-lesion interactions, decreases angiogenesis, and suppresses chemokine-driven inflammation ( Woo et al., 2021 ). In cases of uterine leiomyomas, it inhibits fibrotic remodeling, restores apoptotic balance, and reduces inflammation in the myometrium ( Binmahfouz et al., 2025 ). Furthermore, luteolin helps preserve ovarian reserve in chemotherapy- or toxin-induced POI ( Pan et al., 2025 ), and protects epithelial integrity in cases of endometritis by reducing cytokine-mediated and ferroptotic injury ( Gao et al., 2024 ). Additionally, luteolin exhibits antiproliferative, anti-metastatic, and chemosensitizing effects in ovarian, cervical, and endometrial cancers ( Li et al., 2023 ; Zhao et al., 2023 ; Pei et al., 2024 ). Together, these findings demonstrate that luteolin targets the intersecting molecular pathways that drive multiple reproductive disorders. Despite a strong mechanistic and preclinical foundation, the clinical application of luteolin has been limited by its poor aqueous solubility, extensive phase II conjugation, and low oral bioavailability ( Wang et al., 2024 ; Lv et al., 2025 ). However, recent advances in formulation technologies, such as nanocrystals, polymeric micelles, β-cyclodextrin-metal-organic frameworks, and SNEDDS/S-SNEDDS systems, and metabolically activated prodrugs, have significantly improved its dissolution, stability, metabolic protection, and systemic exposure ( Batool et al., 2020 ; Miao et al., 2021 ; Wu et al., 2024 ; Yang et al., 2024 ). Alongside these developments, international patent activity has increased, indicating growing commercial and scientific interest ( Wei and Ma, 2014 ; Song Kwon and Sun-woo, 2021 ; Jia et al., 2024 ). Despite this progress, most filings remain in early developmental stages and primarily emphasize nutraceutical combinations rather than engineered pharmaceutical formulations. Emerging human studies provide encouraging translational support, showing that luteolin, administered primarily as ultramicronized PEA-luteolin, reduces key inflammatory cytokines (IL-6, IL-1β, TNF-α), mast-cell mediators, and oxidative stress biomarkers ( Cordaro et al., 2020 ; De Luca et al., 2022 ; Di Stadio et al., 2022 ). These effects align closely with mechanisms driving reproductive inflammation, metabolic dysfunction, and fibrotic remodeling. Ongoing Phase II trials ( Buchanan, 2025 ) further underscore luteolin’s therapeutic potential. Therefore, this review aims to synthesize current mechanistic, preclinical, and translational evidence on luteolin across major female reproductive disorders and to evaluate its potential as a multi-target therapeutic candidate. It also integrates advances in formulation science, regulatory developments, and patent activity, and outlines a translational roadmap to guide future clinical development.

Patent analysis provides valuable insights into the developmental maturity of luteolin and the extent to which scientific interest has evolved toward commercial and therapeutic applications. Reviewing these patent filings can identify trends in innovation, highlight gaps in preclinical evidence, and evaluate the potential future direction of luteolin-based interventions in reproductive medicine. Recent years have shown a significant increase in patents related to luteolin for hormone-related and gynecological disorders. This activity is primarily concentrated in the United States, China, and South Korea, and reflects diverse therapeutic directions in gynecological and endocrine disorders ( Table 3 ). International patents involving luteolin for reproductive disorders. Abbreviations: PCOS, polycystic ovary syndrome; CNIPA, china national intellectual property administration; USPTO, united states patent and trademark office; KIPO, korean intellectual property office; POI, primary ovarian insufficiency. Patent data compiled from Google Patents. The patent landscape illustrates an emerging field in translational research. While international interest is increasing, most patent applications are still in the early stages, and have not progressed significantly toward investigational new drug (IND) development or clinical applications. Future patent activity will likely need to shift toward formulation engineering, targeted delivery to reproductive tissues, and the development of semi-synthetic derivatives aimed at overcoming luteolin’s pharmacokinetic limitations. Such advancements could effectively bridge the gap between promising preclinical findings and actual therapeutic options, especially for conditions like leiomyomas and diminished ovarian reserve, for which there are currently no existing patents, despite encouraging biological evidence. Collectively, the current patent landscape reflects strong commercial interest in luteolin’s anti-inflammatory and metabolic properties, yet significant opportunities remain in the areas of reproductive tissue-targeted delivery, fibrotic disorders, and fertility preservation.

A comprehensive literature search was conducted to identify published evidence on the chemistry, pharmacokinetics, mechanisms of action, preclinical activity, clinical data, formulations, and regulatory aspects of luteolin in female reproductive disorders. Electronic databases searched included PubMed®, Scopus®, Web of Science™, ScienceDirect®, Google Scholar®, and patent repositories such as Google Patents, USPTO, CNIPA, and KIPO. Search terms combined (“luteolin” OR “flavone”) with reproductive indications (“PCOS,” “endometriosis,” “uterine fibroids/leiomyomas,” “primary ovarian insufficiency,” “endometritis,” “gynecologic cancers”) and mechanistic keywords (“oxidative stress,” “inflammation,” “fibrosis,” “PI3K/AKT/PTEN,” “Nrf2,” “NF-κB,” “TGF-β,” “drug delivery systems”). Eligible studies included peer-reviewed in vitro , in vivo , translational, clinical studies, and patents published in English from database inception through October 2025. Exclusion criteria were non-scientific sources, conference abstracts without full data, and studies unrelated to reproductive or mechanistic relevance. Patents were grouped by indication and formulation type. Clinical reports were evaluated for dose, duration, formulation matrix, biomarkers, and safety outcomes. This approach ensured a structured and comprehensive synthesis of luteolin’s therapeutic potential in female reproductive medicine.

Although luteolin has not yet been clinically tested in reproductive or gynecological disorders, several human studies across neuroinflammatory, neuroimmune, cognitive, and psychiatric conditions provide important insights into its biological activity, safety, and potential therapeutic relevance. In particular, formulations that combine palmitoylethanolamide (PEA) with luteolin (PEA-LUT) have undergone rigorous clinical evaluation. This body of research offers important translational evidence that aligns with the inflammatory and oxidative mechanisms associated with conditions such as PCOS, endometriosis, uterine leiomyomas, ovarian insufficiency, and endometritis. The earliest controlled human evidence for luteolin’s neuroimmune effects comes from a randomized, double-blind clinical trial that evaluated a complex of PEA-LUT in children with autism spectrum disorder ( Cordaro et al., 2020 ). The treatment resulted in significant improvements in behavioral scores (e.g., ABC, CARS), along with reductions in the levels of circulating IL-6 and TNF-α. Moreover, two clinical studies have examined PEA-LUT for persistent neurological and olfactory dysfunction following COVID-19. The first study was a multicenter, double-blind, randomized, placebo-controlled trial that investigated the effects of daily ultramicronized PEA-LUT (770 mg) combined with olfactory training ( Di Stadio et al., 2022 ). This study found significantly greater improvements in olfactory threshold, discrimination, and identification compared to olfactory training alone. Complementing these results, a 3-month longitudinal study involving individuals with post-COVID-19 syndrome demonstrated that PEA-LUT, whether administered with or without prior olfactory training, significantly improved odor identification scores, reduced instances of parosmia, and alleviated mental clouding ( De Luca et al., 2022 ). Together, these studies confirm that luteolin-containing formulations produce clinically measurable effects on neuroinflammation, neuroimmune dysregulation, mitochondrial redox imbalance, and mast cell-associated pathways. These mechanisms closely overlap with those implicated in reproductive inflammatory disorders such as PCOS, endometriosis, and uterine fibroids. A recent double-blind, placebo-controlled crossover trial evaluated the effects of luteolin supplementation (250 mg taken twice daily for 2 weeks) on neurocognitive performance in healthy adults. The study found that luteolin led to modest yet measurable improvements in short-term and working memory ( Quervain, 2024 ). This indicates that luteolin is bioavailable at standard oral doses and produces measurable central nervous system effects even in healthy individuals. Luteolin is currently being studied in a Phase II double-blind randomized controlled trial at the Maryland Psychiatric Research Center. In this 12-week study, individuals with schizophrenia receive either 300 mg of luteolin twice daily or a placebo. The trial aims to evaluate the effects of luteolin on psychopathology, cognitive function, oxidative stress biomarkers, and inflammatory mediators ( Buchanan, 2025 ). This ongoing study represents a significant advance toward formal clinical development as a neuroimmune-modulating therapy. Despite the absence of gynecology-specific clinical trials, the existing human data strongly align with the molecular and preclinical frameworks described in earlier sections, underscoring luteolin’s feasibility as a candidate for translational development in reproductive medicine. Clinical studies consistently show that formulations containing luteolin can suppress key inflammatory mediators, such as IL-6, IL-1β, TNF-α in humans. For example, open-label trials of dietary luteolin-containing supplements demonstrated reductions in serum IL-6 and TNF-α in children with autism spectrum disorders after 26 weeks of treatment ( Tsilioni et al., 2015 ). Although large randomized controlled trials are lacking, prospective open-label human studies have shown that adaptive behavior improvements with luteolin supplementation were associated with decreased pro-inflammatory cytokines, providing translational evidence for immunomodulatory activity in vivo ( Taliou et al., 2013 ). These mediators are central to the survival of endometriotic lesions, ovarian inflammation in PCOS, fibrotic signaling in leiomyomas, and epithelial injury in endometritis. Epidemiological data further suggest that higher dietary luteolin intake correlates with reduced all-cause and cardiovascular mortality, indicating broader metabolic and inflammatory benefits of luteolin intake in human populations ( Yao and Zhou, 2024 ). Together, these findings provide a strong biological rationale for advancing luteolin into human clinical trials targeting female reproductive disorders.

Luteolin has not yet been approved as a pharmaceutical product for any gynecological indication. However, several formulations are commercially available as dietary supplements in various international and regional markets ( Table 2 ). Despite this broad commercial availability, none of the existing preparations are supported by clinical trials for reproductive or gynecological conditions. These products generally fall into two categories. Luteolin-containing supplements available in global markets. 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.

Luteolin exerts wide-ranging effects across female reproductive disorders through the coordinated regulation of multiple molecular pathways. It does not act through a single high-affinity receptor; instead, it exerts its protective effects through multi-target modulation of key inflammatory, oxidative, fibrotic, and proliferative pathways ( Mahwish et al., 2025 ; Stachelska et al., 2025 ). It interacts weakly with receptors such as ERα/ERβ, but its principal actions arise from regulating intracellular signaling networks including NF-κB, Nrf2, PI3K/AKT, PTEN, and TGF-β/Smad. Although the disease-specific effects differ across PCOS, endometriosis, leiomyomas, POI, endometritis, and gynecologic cancers, these pathological states share overlapping signaling disturbances. Luteolin’s ability to modulate several interconnected nodes within these networks provides a mechanistic rationale for its broad therapeutic potential. This section consolidates the major molecular mechanisms through which luteolin exerts therapeutic effects, highlighting cross-talk among pathways to illustrate its systems-level regulatory profile. 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 Fe 2+ and Cu 2+ , 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 ). Integrated molecular pathways regulated by luteolin. Luteolin exerts multi-target regulatory effects by modulating key interconnected pathways in reproductive tissues. It suppresses PI3K/AKT activation, reduces oxidative stress through Nrf2/KEAP1 stabilization, and inhibits MAPK–NF-κB signaling, leading to decreased pro-inflammatory cytokine expression. Luteolin also attenuates TGF-β1-Smad2/3 phosphorylation to limit fibrotic responses, while interacting with ERα and ERβ to modulate hormone-responsive gene expression. Through these coordinated actions, luteolin restores redox balance, reduces inflammation and fibrosis, and regulates hormone-dependent cellular responses.

Female reproductive disorders remain a major global health challenge, with limited innovative therapeutic options, underscoring the urgent need for multi-target agents capable of addressing the intertwined endocrine, metabolic, inflammatory, and fibrotic pathways that drive disease progression. To our knowledge, this review provides the most integrated synthesis to date of luteolin’s chemical foundations, mechanistic actions, disease-specific effects, formulation advances, regulatory status, and translational implications. Luteolin has been shown to play a significant role in various reproductive disorders, such as PCOS, endometriosis, uterine leiomyomas, POI, endometritis, and gynecologic malignancies. It consistently modulates common pathological processes including oxidative stress, inflammation, fibrosis, metabolic dysfunction, abnormal apoptosis, and hormonal imbalance ( Huang and Zhang, 2021 ; Woo et al., 2021 ; Gao et al., 2024 ; Binmahfouz et al., 2025 ; Pan et al., 2025 ). From a mechanistic standpoint, luteolin affects multiple interconnected pathways including the Nrf2/ARE antioxidant pathway, NF-κB and MAPK inflammatory cascades, PI3K/AKT/PTEN metabolic-survival signaling, TGF-β/Smad fibrotic pathways, and ER/PR hormonal regulation ( Thiruvengadam et al., 2021 ; Khan et al., 2024 ). These comprehensive actions highlight luteolin’s potential as a systems-level regulator that can restore balance among redox, immune, and endocrine functions. Recent advances in formulations such as lipid-based systems, polymeric micelles, β-cyclodextrin-metal-organic frameworks (MOF), and luteolin prodrugs have shown considerable promise in enhancing solubility, oral bioavailability, metabolic stability, and tissue exposure ( Liu et al., 2021 ; Miao et al., 2021 ; Wu et al., 2024 ; Yang et al., 2024 ). Growing patent activity further reflects translational interest, although major gaps remain in targeted delivery and leiomyoma- or fertility-specific applications. Early human studies from neuroimmune and post-COVID populations demonstrate luteolin’s anti-inflammatory and antioxidant activity ( Cordaro et al., 2020 ; De Luca et al., 2022 ; Di Stadio et al., 2022 ), suggesting potential relevance to reproductive disorders characterized by similar inflammatory profiles. To advance luteolin toward clinical application, future research should follow a structured translational roadmap. First, comprehensive pharmacokinetic and metabolite-profiling studies are needed to identify whether therapeutic activity is driven primarily by the aglycone form or its glucuronidated and sulfated metabolites. Parallel efforts should prioritize uterus- and ovary-targeted delivery platforms, including nanocarriers, lipid systems, and prodrug strategies, to enhance tissue specificity and reduce interindividual variability. Standardizing preclinical models, dosing strategies, biomarkers, and follow-up durations will be essential for improving reproducibility and supporting meta-analytic interpretation. Building on these foundations, early-phase clinical trials in PCOS, endometriosis, and leiomyomas should prioritize subgroups with high oxidative, inflammatory, metabolic, or fibrotic burden. Finally, expanding the innovation pipeline through prodrug development, synergistic combination therapies, and patentable formulation strategies will help overcome current pharmacokinetic challenges and accelerate translation. This roadmap ( Figure 3 ) highlights the essential steps needed to advance luteolin from promising preclinical evidence toward human therapeutic development. Translational roadmap for luteolin in female reproductive disorders. A schematic summary of the key steps necessary to advance luteolin toward clinical application. It includes pharmacokinetic and metabolite profiling, targeted delivery strategies for the uterus and ovaries, standardized preclinical models, and early-phase clinical trials for conditions such as PCOS, endometriosis, and leiomyoma. Additionally, it highlights innovations through the development of prodrugs, combination therapies, and patentable formulations. In conclusion, luteolin is a biologically versatile flavone with a complex mechanism of action, showing significant potential to address unmet therapeutic needs in female reproductive medicine. Its consistent efficacy across preclinical models, together with emerging translational evidence, provides a strong rationale for further investigation. Future progress will depend on integrating advances in pharmacology, formulation science, reproductive biology, and clinical research. With sustained interdisciplinary collaboration, luteolin has the potential to evolve from an underrecognized nutraceutical into a rigorously validated therapeutic platform with meaningful impact on women’s reproductive health and quality of life.

Preclinical investigations consistently demonstrate that luteolin is well tolerated across multiple experimental systems. In rodent studies, oral dosing has shown a wide margin of tolerance, with no adverse alterations in hematological or biochemical parameters even at repeated administrations, and only transient gastrointestinal effects reported at higher exposures ( Abdrabou et al., 2024 ). Comparable findings were observed in mice, where systemic administration did not produce detectable hepatic or renal abnormalities, and histological examination confirmed preserved tissue architecture following multi-week treatment protocols ( Mugale et al., 2024 ). Complementary in vitro assessments further indicate that luteolin exhibits minimal cytotoxicity toward non-malignant cells at concentrations typically required for anti-inflammatory or antioxidant actions, supporting a favorable biological response profile ( Tuli et al., 2022 ). Short-term human data also support luteolin’s tolerability. Clinical studies using ultramicronized PEA-LUT have administered 100–600 mg/day luteolin equivalents for 2–12 weeks without any serious adverse events ( Cordaro et al., 2020 ; De Luca et al., 2022 ; Di Stadio et al., 2022 ). Trials consistently report only mild, transient gastrointestinal discomfort or headaches, with no hepatotoxic, nephrotoxic, hematologic, or systemic toxicity. A placebo-controlled trial administering 250 mg luteolin twice daily in healthy adults likewise showed excellent tolerability with no clinically meaningful adverse events ( Quervain, 2024 ). Several pharmacokinetic considerations warrant attention. Luteolin undergoes extensive UGT- and SULT-mediated phase II metabolism, raising the potential for drug-drug interactions with medications using the same metabolic pathways ( Quintieri et al., 2008 ; Wang et al., 2024 ). In vitro assays also document inhibitory effects on CYP1A2, CYP2C9, and CYP3A4, suggesting that high-dose or chronic exposure may alter the pharmacokinetics of drugs with narrow therapeutic windows ( Kaci et al., 2023 ). Although the clinical significance of these interactions remains undetermined, these findings highlight the need for formal pharmacokinetic studies. From a regulatory standpoint, luteolin-containing products are globally classified as dietary or nutraceutical supplements rather than therapeutic agents. In the United States, they fall under the Dietary Supplement Health and Education Act (DSHEA) of 1994, and do not require FDA pre-market approval. In Saudi Arabia, the Saudi Food and Drug Authority (SFDA) regulates luteolin-based products as food supplements in accordance with the Products Classification Guidance (Version 7, 2024). The European Food Safety Authority (EFSA) lists luteolin as a conventional botanical ingredient with no approved health claims. Similarly, Health Canada categorizes it as a natural health product and the Australian Therapeutic Goods Administration (TGA) includes it among permissible ingredients for complementary medicines. Overall, luteolin is well tolerated in animals and humans, with a low incidence of adverse events at clinically relevant doses. Nonetheless, rigorous GLP-compliant toxicology, drug-interaction studies, and reproductive health–focused clinical trials are needed to fully define long-term safety and support its development for gynecologic indications.