Formononetin alleviates ovarian fibrosis and inflammation via targeting SOCS3 and inhibiting TGF-β1/Smad signaling in PCOS
Abstract
Objective: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by ovulatory dysfunction. Formononetin (FMN), a bioactive compound derived from leguminous plants, including Glycyrrhiza uralensis, Trifolium pratense, and Astragalus membranaceus, exhibits anti-inflammatory and anti-fibrotic properties. This study aimed to evaluate the therapeutic effects of FMN in a PCOS rat model and elucidate its underlying molecular mechanisms.
Methods: A PCOS-like model was established in 3-week-old female Sprague-Dawley rats by daily dehydroepiandrosterone (DHEA) injections. The efficacy of FMN was assessed by monitoring estrous cycles, hormone levels, glucose tolerance, and ovarian tissue morphology. Network pharmacology and transcriptome sequencing were used to predict the molecular targets and signaling pathways of FMN. The binding and stabilizing effects of FMN on suppressor of cytokine signaling 3 (SOCS3) were confirmed using molecular docking, molecular dynamics (MD) simulations, and cellular thermal shift assay (CETSA)-Western blotting (WB) (CETSA-WB). The expression of SOCS3, inflammation- and fibrosis-related markers, and the components of the transforming growth factor beta1 (TGF-β1)/Smad pathway were quantified by quantitative polymerase chain reaction (qPCR), WB, and immunohistochemistry. Functional validation was performed using SOCS3 small interfering RNA (siRNA).
Results: DHEA successfully induced a PCOS-like phenotype, including disrupted…
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