Harnessing natural herbaceous plants against ferroptosis: Implications for managing polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by ovulatory dysfunction, hyperandrogenism, and insulin resistance. It results from complex genetic and environmental factors and progressively impairs reproductive and metabolic health. Natural phytotherapy provides holistic regulation through multiple components and targets and is recognized for its favorable safety profile, including low organ toxicity. Consequently, it represents a promising avenue for comprehensive PCOS management. This review aims to comprehensively analyze the ethnopharmacological applications of natural herbs in modulating ferroptosis within the context of PCOS. This study systematically reviewed natural herbal interventions for PCOS, with a focus on their mechanisms in regulating ferroptosis. It consulted traditional medical classics, ethnomedicinal records, and clinical literature, and searched databases including PubMed and the China National Knowledge Infrastructure (CNKI). Keywords such as "PCOS," "ferroptosis," "natural herbal medicines," "traditional Chinese medicine (TCM) compound preparations," "single-herb extracts," and "plant active ingredients" were used to retrieve research from ethnobotany, phytochemistry, and pharmacology. Recent relevant publications were comprehensively collected and analyzed. Integrating natural herbal medicines into the comprehensive management of PCOS offers several advantages, which can be primarily explained from two perspectives. First, the pathological mechanisms of PCOS involve multiple interconnected biological processes, including hormonal imbalance, insulin resistance, oxidative stress, and chronic inflammation. The onset and progression of PCOS are closely linked to cell death pathways such as ferroptosis and are regulated by various molecular pathways, including GPX4/COX2, SLC7A11/GPX4, circ_0097636/miR-186-5p/SIRT3, and AMPK/Nrf2 signaling. Drugs targeting a single molecule often struggle to effectively regulate such a complex network. In contrast, various herbal medicines and their active components-such as platycodin D, nuciferine (NF), baicalein, and berberine (BBR)-exhibit multi-target properties, enabling them to simultaneously modulate key molecules involved in ferroptosis in PCOS, including GPX4, SLC7A11, COX2, FTH1, ACSL4, and ferritin. This allows for synergistic intervention in multiple pathological processes of the disease. Additionally, natural herbal medicines and their active components have demonstrated a high level of safety with long-term use, particularly exhibiting relatively lower risks of liver and kidney toxicity. They offer certain advantages compared to traditional hormones or insulin sensitizers. For example, classic compound prescriptions such as Wenshen Tiaojing decoction (WSTJD), Shoutai pill, and Erchen decoction are commonly used in TCM clinical practice to regulate menstruation, improve insulin resistance, and promote ovulation, supported by extensive practical evidence. In recent years, to clarify their scientific basis, an increasing number of studies have extracted key active components from these effective compound formulations using modern separation techniques. With the aid of cell and animal experiments, researchers have thoroughly elucidated the mechanisms by which these components improve PCOS through pathways such as the regulation of ferroptosis, thereby bridging traditional knowledge and modern pharmacology. Traditional Chinese compound formulations hold significant promise for developing drugs targeting PCOS. Notably, certain prescriptions and herbal extracts that focus on regulating ferroptosis as a key mechanism are attracting increasing attention and research within the academic community.