Luteolin and its analog luteolin-7-methylether from Leonurus japonicus Houtt suppress aromatase-mediated estrogen biosynthesis to alleviate polycystic ovary syndrome by the inhibition of tumor progression locus 2

• Published in: Journal of ethnopharmacology 2024-09, Vol.331, p.118279, Article 118279
• Main Authors: Shi, Xiao-ke, Peng, Ting, Azimova, Bahtigul, Li, Xiao-li, Li, Shan-shan, Cao, Dong-yi, Fu, Nai-jie, Zhang, Guo-lin, Xiao, Wei-lie, Wang, Fei
• Format: Article
• Language: English
• Subjects: Animals; Aromatase; Aromatase - genetics; Aromatase - metabolism; Aromatase Inhibitors - isolation & purification; Aromatase Inhibitors - pharmacology; Estrogen biosynthesis; Estrogens - biosynthesis; Estrogens - pharmacology; Female; Granulosa Cells - drug effects; Granulosa Cells - metabolism; Humans; Leonurus - chemistry; Luteolin; Luteolin - isolation & purification; Luteolin - pharmacology; Mice; Polycystic ovary syndrome; Polycystic Ovary Syndrome - drug therapy; Polycystic Ovary Syndrome - metabolism; Tumor progression locus 2
• ISSN: 0378-8741; 1872-7573; 1872-7573
• DOI: 10.1016/j.jep.2024.118279

Leonurus japonicus Houtt (L. japonicus, Chinese motherwort), known as Yi Mu Cao which means “good for women”, has long been widely used in China and other Asian countries to alleviate gynecological disorders, often characterized by estrogen dysregulation. It has been used for the treatment of polycystic ovary syndrome (PCOS), a common endocrine disorder in women but the underlying mechanism remains unknown. The present study was designed to investigate the effect and mechanism of flavonoid luteolin and its analog luteolin-7-methylether contained in L. japonicus on aromatase, a rate-limiting enzyme that catalyzes the conversion of androgens to estrogens and a drug target to induce ovulation in PCOS patients. Estrogen biosynthesis in human ovarian granulosa cells was examined using ELISA. Western blots were used to explore the signaling pathways in the regulation of aromatase expression. Transcriptomic analysis was conducted to elucidate the potential mechanisms of action of compounds. Finally, animal models were used to assess the therapeutic potential of these compounds in PCOS. Luteolin potently inhibited estrogen biosynthesis in human ovarian granulosa cells stimulated by follicle-stimulating hormone. This effect was achieved by decreasing cAMP response element-binding protein (CREB)-mediated expression of aromatase. Mechanistically, luteolin and luteolin-7-methylether targeted tumor progression locus 2 (TPL2) to suppress mitogen-activated protein kinase 3/6 (MKK3/6)-p38 MAPK-CREB pathway signaling. Transcriptional analysis showed that these compounds regulated the expression of different genes, with the MAPK signaling pathway being the most significantly affected. Furthermore, luteolin and luteolin-7-methylether effectively alleviated the symptoms of PCOS in mice. This study demonstrates a previously unrecognized role of TPL2 in estrogen biosynthesis and suggests that luteolin and luteolin-7-methylether have potential as novel therapeutic agents for the treatment of PCOS. The results provide a foundation for further development of these compounds as effective and safe therapies for women with PCOS. [Display omitted] •Luteolin reduced FSH-induced estrogen biosynthesis by inhibiting aromatase expression.•Luteolin and luteolin-7-methylether targeted TPL2 to suppress MAPK-CREB pathway signaling.•Luteolin and luteolin-7-methylether inhibited phosphorylation of TPL2 to reduce aromatase expression.•Luteolin and luteolin-7-methylether effectively alleviated the