ATG4C (autophagy related 4C cysteine peptidase) is a cysteine protease that plays a specialized role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. The enzyme cleaves the C-terminal amino acid of ATG8 proteins including MAP1LC3 and GABARAPL2 to expose a C-terminal glycine, which is essential for their conjugation to phosphatidylethanolamine and membrane insertion 1. Compared to ATG4B, ATG4C displays weaker ability to cleave ATG8 proteins but stronger delipidation activity, catalyzing removal of PE-conjugated forms of ATG8 proteins during macroautophagy 1. Notably, ATG4C is weakly involved in phagophore growth during mitophagy, distinguishing it from other ATG4 family members 2. ATG4C has emerged as a susceptibility gene in multiple diseases. Genetic association studies directly implicate ATG4C in Crohn's disease through coding variants and increased rare variant burden 3. In Kashin-Beck Disease, ATG4C variants associate with reduced mRNA and protein expression in affected chondrocytes, suggesting defective autophagy contributes to pathogenesis 4. In epithelial ovarian cancer, elevated ATG4C mRNA expression independently predicts shorter overall survival, establishing it as a prognostic biomarker 5. During cardiac ischemia-reperfusion injury, ATG4C expression is significantly upregulated as part of the autophagy response 6. ATG4C also participates in sodium-enhanced antibacterial autophagy in macrophages 7.