ATG4C is a cysteine protease that plays a specialized role in autophagy, the cellular degradation pathway essential for maintaining tissue homeostasis. The enzyme catalyzes two key functions: proteolytic activation of ATG8 family proteins (such as MAP1LC3 and GABARAPL2) by cleaving their C-terminal amino acid to expose a critical glycine residue, and delipidation—removal of phosphatidylethanolamine from ATG8 proteins during autophagosome maturation [UniProt]. Compared to ATG4B, the primary activator of ATG8 proteins, ATG4C shows weaker C-terminal cleavage activity but stronger delipidation capability, and is weakly involved in mitophagy (selective autophagy of damaged mitochondria) 1. Recent evidence indicates ATG4C regulates antibacterial autophagy in macrophages through HIF1A signaling 2. ATG4C variants associate with multiple diseases. In Crohn's disease, a significantly increased burden of rare coding variants in ATG4C was identified in affected patients, highlighting autophagy dysregulation in intestinal inflammation 3. Kashin-Beck disease (a degenerative joint disorder) shows genetic association with ATG4C SNPs and reduced ATG4C expression in affected chondrocytes 4. In epithelial ovarian cancer, elevated ATG4C expression independently predicts shorter overall survival 5. During cardiac ischemia-reperfusion injury, ATG4C expression increases as part of a protective autophagy response 6.