A Guide to autophagy-dependent cell death: concepts, criteria, and mechanisms.

Abstract

Macroautophagy (hereafter referred to as autophagy) is generally regarded as a cytoprotective process that maintains cellular homeostasis through intracellular recycling and metabolic adaptation. However, under certain conditions, autophagic machinery can contribute directly to cell death. Defining when autophagy functions as a cause rather than a consequence of cellular demise remains a major challenge and complicates the concept of autophagy-dependent cell death (ADCD). Experimental studies indicate that ADCD can occur through multiple mechanisms, including excessive self-digestion, autophagy-dependent lysosomal injury, selective autophagy-mediated degradation of critical cellular components, and specialized death programs such as autosis. These processes intersect extensively with apoptosis, necroptosis, ferroptosis, and pyroptosis, placing ADCD within a broader network of regulated cell death pathways. Evidence from cancer, neurodegenerative, cardiovascular, and inflammatory diseases further suggests that ADCD contributes to pathogenesis and may provide therapeutic opportunities. In this review, we discuss the criteria for defining ADCD, the molecular mechanisms underlying its execution, its interactions with other cell death pathways, and its relevance to human disease. Together, we propose a practical framework for distinguishing bona fide ADCD from cell death merely accompanied by autophagy and provide guidance for establishing autophagy as a causal component of the death process.