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

Female reproductive disorders represent a major global health challenge. Despite their clinical heterogeneity, these conditions share core pathological mechanisms including oxidative stress, chronic inflammation, hormonal imbalance, metabolic dysfunction, extracellular matrix remodeling, and dysregulated cell survival. Current therapies rarely target these interconnected processes, underscoring the need for multi-pathway modulators. Luteolin, a dietary flavone, has emerged as a promising candidate due to its regulatory effects on redox balance, NF-κB/MAPK signaling, PI3K/AKT/PTEN pathways, TGF-β/Smad-mediated fibrosis, and estrogen and progesterone receptor activity. Preclinical and mechanistic evidence demonstrates luteolin's benefits across major reproductive disorders. In PCOS, it improves insulin sensitivity, supports ovulatory function, modulates hepatic and ovarian gene expression, and influences gut microbiota. In endometriosis, it disrupts epithelial-macrophage crosstalk, reduces chemokine-driven inflammation, and inhibits angiogenesis and lesion growth. In leiomyomas, luteolin attenuates fibrosis and normalizes apoptotic and TGFB1/PI3K/PTEN signaling. Protective effects on ovarian reserve in primary ovarian insufficiency, anti-inflammatory and anti-ferroptotic actions in endometritis, and suppression of sFlt-1 and HIF-1α in preeclampsia further highlight its relevance to reproductive pathology. Anticancer and chemosensitizing effects have also been reported in ovarian, cervical, and endometrial cancers. Although clinical translation is constrained by poor solubility and bioavailability, emerging nanocarrier and prodrug strategies markedly improve luteolin's pharmacokinetic profile. Human studies of luteolin-based formulations support anti-inflammatory and antioxidant effects consistent with reproductive disease mechanisms. Overall, luteolin represents a multi-target pharmacological candidate with translational potential in gynecologic and endocrine disorders, warranting further optimization and early-phase clinical investigation.