Yangjing Zhongyu decoction ameliorates polycystic ovary syndrome via multi-organ ferroptosis inhibition: A mechanistic study.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Yangjing Zhongyu decoction (YZD), a traditional Chinese herbal formula, shows promise for treating polycystic ovary syndrome (PCOS), but its mechanisms of action remain unclear. Ferroptosis has emerged as a potential contributor to PCOS. AIM OF THE STUDY: To determine YZD's effects on PCOS by regulating ferroptosis in multiple organs. MATERIALS AND METHODS: Dihydrotestosterone (DHT)-induced PCOS mice received YZD treatment at low/medium/high doses. We assessed metabolic (body weight, glucose tolerance, hepatic steatosis) and reproductive (estrous cycles, hormones, histology) parameters. Ferroptosis markers and related genes were analyzed in the liver, ovary, and uterus. RESULTS: YZD significantly improved both metabolic dysfunction (reduced body weight, improved glucose tolerance) and reproductive abnormalities (restored estrous cyclicity, normalized ovarian morphology). Mechanistically, YZD demonstrated consistent upregulation of glutathione peroxidase 4 (GPX4) in all tissues and downregulation of 4-hydroxynonenal (4HNE) in liver and uterine tissues. The effects on iron metabolism and mitochondrial function showed tissue-specific patterns. In liver tissue, YZD downregulated pro-ferroptotic genes (Slc1a5, Gls2, Cs, Tfrc, and Ireb2) and Slc7a11, and upregulated protective factors (Fth1, Ftl1, Fpn1, and Ho1). Ovarian tissue exhibited downregulation of Slc1a5, Tfrc, Ireb2, and Fpn1 along with upregulation of Gclc, Gss, and Ftl1. In the uterus, YZD treatment decreased the expression of Slc1a5, Cs, and Ireb2 and increased the expression of Slc7a11 and Gss. CONCLUSIONS: YZD ameliorates PCOS by inhibiting ferroptosis in multiple organs, primarily via GPX4 activation and iron homeostasis regulation, thus supporting its potential as a natural therapeutic for PCOS.