ATG4D (autophagy related 4D cysteine peptidase) is a member of the ATG4 protease family that regulates autophagy through processing of Atg8-family proteins, particularly GABARAP-L1 1. Beyond its canonical role in autophagosome formation, ATG4D promotes phagophore growth and ATG9A vesicle trafficking to mitochondria independently of its protease activity 2. Notably, ATG4D functions as an autophagy regulator linking mitochondrial dysfunction with apoptosis; caspase-3 cleavage of ATG4D enhances its processing activity and triggers mitochondrial recruitment during apoptosis 1. Genetic variations in ATG4D are implicated in heritable neurodevelopmental disorders, with loss-of-function models in zebrafish and mice supporting a neuroprotective role 3. A genome-wide association study identified ATG4D variants associated with susceptibility to anti-GAD65 autoimmune neurological syndromes, with differential CSF proteome expression in affected patients 4. In cardiac ischemia-reperfusion injury, ATG4D expression is upregulated as part of an adaptive autophagy response 5. Clinically, elevated ATG4D expression in osteosarcoma tissues correlates with poor overall survival and promotes tumor cell proliferation, migration, and drug resistance; ATG4D knockdown sensitizes osteosarcoma cells to chemotherapy-induced death 6. Conversely, defective ATG4D expression in uterine fibroids impairs autophagy flux and promotes abnormal cell proliferation 7, suggesting context-dependent roles in disease pathogenesis.