Kummerowia striata extract ameliorates polycystic ovary syndrome and associated hepatic metabolic dysfunction in mice: an integrated network-pharmacology and lipidomics study of the HIF-1α signaling axis

Context Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women of reproductive age and a major contributor to infertility. Kummerowia striata (Ks) is a plant of medicinal and dietary significance. Although its extract has demonstrated beneficial effects on animal reproduction, the underlying mechanism in PCOS has yet to be elucidated. Aim of the study This study aims to systematically investigate the preventive potential and underlying mechanisms of Ks in PCOS-related infertility by integrating network pharmacology and lipidomics with in vitro and in vivo models. Methods A PCOS model was established in KM mice using letrozole combined with a high-fat diet. The preventive/co-treatment effects of Ks (administered concurrently with letrozole induction) were evaluated through histopathological analysis, hormone level assessment, inflammatory factor measurement, and serum biochemical markers. Integrated network pharmacology, untargeted lipidomics, and molecular biology techniques (qPCR, Western blot, immunofluorescence) were employed to elucidate the underlying mechanisms. Lipopolysaccharide (LPS) and testosterone propionate (TP)-induced KGN cells, gene knockdown models, and ovarian explant cultures were utilized to further validate the efficacy and molecular pathways of Ks at the cellular level. Results Untargeted lipidomics analysis identified 919 differential lipids between the PCOS group and control mice. Among them, high-dose Ks restored 79 lipids to near-control levels (74 upregulated and 5 downregulated), with enrichment in thermogenesis, glycerolipid metabolism and insulin resistance pathways. Network pharmacology and immunoblotting highlighted HIF-1α signaling, together with PTGS2 and related inflammatory and glycolytic proteins. In LPS- or TP-treated KGN cells, Ks attenuated inflammation and corrected glycolytic abnormalities. GAPDH knockdown suggested a possible role for this enzyme in testosterone secretion and glycolytic flux under hyperandrogenic conditions. Ks also alleviated hepatic inflammation and oxidative stress in PCOS mice. Together, these findings indicate that Ks mitigates PCOS and associated hepatic metabolic dysfunction in association with altered HIF-1α signaling and lipid metabolic reprogramming.