ATG4A is a cysteine protease that plays dual roles in autophagy regulation through both proteolytic and non-proteolytic mechanisms. The protein's primary function involves processing ATG8 family proteins (LC3/GABARAP) by cleaving their C-terminal amino acids to expose glycine residues, which is essential for their conjugation to phosphatidylethanolamine and membrane insertion during autophagosome formation 1. ATG4A also mediates delipidation of PE-conjugated ATG8 proteins, showing stronger delipidation activity compared to ATG4B 1. Beyond its proteolytic functions, ATG4A promotes phagophore growth independently of its protease activity by regulating ATG9A trafficking to mitochondria and facilitating phagophore-endoplasmic reticulum contacts during lipid transfer 1. The protein demonstrates tissue-specific importance, being selectively upregulated in maturing human erythroid cells where its depletion impairs red blood cell production, terminal differentiation, and mitochondrial clearance 2. ATG4A expression is regulated by epigenetic mechanisms, with KMT2A promoting METTL3 expression through H3K4me3 modification, while METTL3-mediated m6A modification reduces ATG4A RNA stability 3. Clinical relevance includes upregulation during cardiac ischemia-reperfusion injury 4 and involvement in glioblastoma cholesterol homeostasis through lipophagy regulation 5.