Therapeutic potential of luteolin in central precocious puberty: insights from a danazol-induced rat model

Abstract

Background: Recently, central precocious puberty (CPP) is becoming a major public health concern worldwide due to its enhanced prevalence. Traditional Chinese medicine (TCM) compounds offer unique therapeutic advantages for treating this condition, and luteolin, a bioactive monomer compound commonly found in these herbs, has drawn increasing attention. However, the therapeutic effects of luteolin on CPP development remain unclear.

Methods: A danazol-induced CPP model was established in Sprague-Dawley rats to explore the potential therapeutic effects of luteolin. Sexual development indicators, organ coefficients, gonadal histopathology, and sex hormone levels were evaluated to assess treatment outcomes. Additionally, a comprehensive approach involving network pharmacology, molecular docking, and transcriptomic analyses was used to identify luteolin-related signaling pathways and target proteins involved in CPP treatment. Finally, we carried out enzyme-linked immunosorbent assay (ELISA) and reverse transcription- quantitative polymerase chain reaction (RT-qPCR) for finding validation and exploring the underlying mechanisms.

Results: In the danazol-induced CPP model, luteolin treatment significantly decreased the abundances of Estradiol (E2), luteinizing hormone serum, and follicle-stimulating hormone in sera; reduced organ coefficients and ovarian and uterine wet weights; and delayed vaginal opening. Network pharmacology and transcriptomic analyses revealed that luteolin exerted its therapeutic effects mainly by modulating immune and inflammatory pathways, including the tumor necrosis factor-α, Toll-like receptor, and IL-17 signaling pathways. Molecular docking demonstrated stable binding of luteolin to key targets such as Cxcl10, Cxcl11, Stat1, Tlr3, and Irf7. ELISA results confirmed that luteolin inhibited pro-inflammatory cytokines while promoting anti-inflammatory factors in the CPP model. Furthermore, RT-qPCR analysis revealed that luteolin enhanced Irf7 and Stat1 expression within the Toll-like receptor pathway, mainly by upregulating Tlr3, thereby enhancing the abundances of downstream effector molecules Cxcl10 and Cxcl11.

Conclusion: This study is the first to determine that luteolin ameliorates CPP via the Toll-like receptor signaling pathway. These findings enhance our understanding of luteolin's pharmacological actions and support its potential role in CPP treatment.

Keywords: children; danazol; luteolin; precocious puberty; reverse transcription- quantitative polymerase chain reaction; transcriptomics.