Cell death pathways in the pathogenesis of depression: mechanisms and therapeutic implications

Depression is a highly prevalent and disabling psychiatric disorder with a complex and incompletely understood pathophysiology. Increasing evidence implicates regulated cell death (RCD), including apoptosis, necroptosis, pyroptosis, and ferroptosis, in neuronal vulnerability, synaptic impairment, and circuit dysfunction associated with depression. This review provides a comprehensive overview of the current understanding of distinct cell death modalities in animal models of depression and human brain tissues, with particular emphasis on their molecular mechanisms and pathological consequences. We further discuss the intricate interactions between cell death pathways and key pathological processes implicated in depression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired neurotrophic support. In addition, we summarize emerging therapeutic strategies targeting cell death-associated signaling pathways, including pharmacological inhibition of specific cell death programs and modulation of shared upstream regulators. By integrating recent advances in molecular neuroscience and psychiatric research, this review provides a conceptual framework for elucidating the cellular mechanisms underlying depression and to highlight potential targets for the development of novel antidepressant therapies.