Autophagy-Dependent Ferroptosis in Cancer

Significance: Autophagy is a self-degrading process that determines cell fate in response to various environmental stresses. In contrast to autophagy-mediated cell survival, the signals, mechanisms, and effects of autophagy-dependent cell death remain obscure. The discovery of autophagy-dependent ferroptosis provides a paradigm for understanding the relationship between aberrant degradation pathways and excessive lipid peroxidation in driving regulated cell death.Recent Advances: Ferroptosis was originally described as an autophagy-independent and iron-mediated nonapoptotic cell death. Current studies reveal that the level of intracellular autophagy is positively correlated with ferroptosis sensitivity. Selective autophagic degradation of proteins (e.g., ferritin, SLC40A1, ARNTL, GPX4, and CDH2) or organelles (e.g., lipid droplets or mitochondria) promotes ferroptosis by inducing iron overload and/or lipid peroxidation. Several upstream autophagosome regulators (e.g., TMEM164), downstream autophagy receptors (e.g., HPCAL1), or danger signals (e.g., DCN) are selectively required for ferroptosis-related autophagy, but not for starvation-induced autophagy. The induction of autophagy-dependent ferroptosis is an effective approach to eliminate drug-resistant cancer cells.Critical Issues: How different organelles selectively activate autophagy to modulate ferroptosis sensitivity is not fully understood. Identifying direct protein effectors of ferroptotic cell death remains a challenge.Future Directions: Further understanding of the molecular mechanics and immune consequences of autophagy-dependent ferroptosis is critical for the development of precision antitumor therapies.