DEPP1 (DEPP autophagy regulator 1) is a mitochondrial protein that functions as a critical modulator of autophagy and cellular stress responses. Mechanistically, DEPP1 activates mitochondrial autophagy via FOXO3-dependent pathways and BCL2 interacting protein 3, operating through increased cellular ROS to promote autophagic flux 1. Under stress conditions including hypoxia, oxidative stress, and starvation, DEPP1 expression is induced in a HIF-dependent manner and localizes to mitochondria where it regulates selective autophagy of damaged organelles 21. DEPP1 has emerged as a pathologically relevant gene across multiple diseases. In ischemic cardiomyopathy, HIF-induced DEPP1 mediates mitochondrial loss, lipid accumulation, and cardiac dysfunction; DEPP1 loss improves cardiomyocyte survival and reduces cardiac remodeling 2. In gastric cancer, elevated DEPP1 expression associates with poor prognosis, stroma-rich immunosuppressive microenvironments, and chemotherapy resistance 3. DEPP1 is upregulated in fast/glycolytic muscle fibers during aging and obesity, contributing to muscle atrophy through inflammatory pathways 4. Additionally, DEPP1 serves as a FOXO1-target gene induced during starvation-induced muscle atrophy 5, and appears elevated in pathological vascular smooth muscle proliferation and glioma progression 67. In osteoarthritis, DEPP1 loss exacerbates cartilage degradation by impairing mitochondrial autophagy 1. DEPP1 represents a potential therapeutic target for diseases involving autophagic dysfunction.