Yulong Zhao

Depression is a widespread mental disorder whose impact on an individual’s health extends far beyond the psychological dimension. As a disease with a significant burden, the effective treatment of depression has become a major challenge for global public health. Although several hypotheses have been proposed for the pathogenesis of depression, its pathophysiological mechanisms remain complex and not yet fully understood. Recent studies suggest that dysfunctional autophagy may play an important role in the development of depression. Autophagy, as an important intracellular degradation mechanism, maintains neuronal function and health by removing excess proteins and damaged organelles. Current evidence suggests that the regulation of autophagic processes may provide new potential targets for the treatment of depression. In this paper, we review the pharmacological mechanisms of autophagy by different antidepressant drugs and the abnormal changes in autophagy in patients with depression and in multiple models. Importantly, we focus on the role of autophagy in different pathological mechanisms of depression and discuss current limitations as well as potential directions for future research.

Emerging evidence links ferroptosis–mitochondrial dysregulation to depression pathogenesis through an oxidative stress–energy deficit–neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal–hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a “ferroptosis–mitochondrial fragmentation–metabolic maladaptation” triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability—a framework with significant implications for developing neuroprotective antidepressants.