Emerging cell death in depression: Mechanisms and therapeutic implications

Major depressive disorder (MDD) is a highly prevalent psychiatric condition and a leading cause of disability worldwide. Despite extensive research, incomplete elucidation of its underlying pathological and pharmacological mechanisms continues to hinder the development of effective diagnostic and therapeutic strategies, resulting in unsatisfactory treatment outcomes for a substantial proportion of patients. Therefore, the identification of novel molecular targets and therapeutic approaches remains a critical priority in MDD research. Ferroptosis, pyroptosis, and cuproptosis represent emerging forms of regulated cell death (RCD) that have garnered increasing attention in neurological and psychiatric disorders. Growing evidence indicates that ferroptosis and pyroptosis are closely involved in both the pathogenesis of MDD and its therapeutic modulation. This article reviews the molecular mechanisms of emerging RCD pathways and their roles in the pathogenesis and treatment of MDD. The review primarily focuses on natural products and traditional Chinese medicine that target these pathways, with most evidence derived from preclinical studies. It seeks to shed new light on disease mechanisms and potential therapeutic strategies.