Nrf2-related pathogenesis of premature ovarian insufficiency and traditional Chinese medicine-based interventions

Premature ovarian insufficiency (POI) is a complex reproductive disorder characterized by diminished ovarian reserve and impaired ovarian endocrine function before the age of 40 years. Increasing evidence indicates that oxidative stress plays a pivotal role in POI pathogenesis by inducing mitochondrial dysfunction, DNA damage, inflammatory responses, ferroptosis, and granulosa cell apoptosis, ultimately accelerating follicular depletion. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular antioxidant defense, is essential for maintaining ovarian redox homeostasis and protecting reproductive function. Recent advances have demonstrated that traditional Chinese medicine (TCM), including herbal medicines, bioactive metabolites, classical formulations, and acupuncture therapies, exerts protective effects against POI by modulating Nrf2-associated signaling networks, thereby enhancing antioxidant enzyme expression, improving mitochondrial function, reducing oxidative DNA damage, suppressing inflammation and apoptosis, and preserving follicular development. This review summarizes the pathological role of oxidative stress and Nrf2 signaling in POI, and discusses the current progress of TCM interventions modulating the Nrf2 pathway, including their molecular mechanisms and therapeutic potential. Furthermore, the limitations of current research, including the lack of clinically representative models, limited understanding of molecular targets, and insufficient evidence from well-designed clinical studies, are highlighted. Future studies integrating multi-omics approaches, precision medicine, and evidence-based clinical trials are warranted to further elucidate the regulatory networks of TCM-mediated Nrf2 activation and promote the clinical translation of TCM strategies for POI prevention and treatment.