Emerging mechanisms of ATG8-independent non-canonical autophagy

ATG8-independent autophagy represents an emerging field of cellular degradation that challenges the long-held view that LC3/GABARAP lipidation is universally required for autophagosome formation and autophagic flux. Over the past decade, studies across mammals, plants, and protozoa have revealed that cells can execute degradative mechanisms through alternative macroautophagy, microautophagy-like pathways, and autophagy-like systems that operate with reduced or absent reliance on ATG8 proteins. These discoveries have reshaped the conceptual framework of autophagy by separating membrane biogenesis, cargo sequestration, and lysosomal delivery into potentially ATG8-uncoupled modules. ATG8-independent pathways are now recognized as important for stress adaptation, organelle quality control, developmental remodeling, and selective cargo degradation. This review summarizes the historical development, mechanistic diversity, and biological relevance of ATG8-independent autophagy, and discusses its implications for disease biology and therapeutic targeting. Understanding these unconventional pathways will be essential for a complete view of autophagic regulation in health and disease.