Autophagy-Dependent Ferroptosis: Machinery and Regulation

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved cellular process capable of degr.:.:!ing various biological molecules (e.g., protein, glycogen, lipids, DNA, and RNA) and organelles (e.g., mitochondria, endoplasmic reticulum [ER] ribosomes, lysosomes, and micronuclei) via the lysosomal pathway. Ferroptosis is a type of oxidative stress-dependent regulated cell death associated with iron accumulation and lipid peroxidation. The recently discovered role of autophagy, especially selective types autophagy (e.g., ferritinophagy, lipophagy, clockophagy, and chaperone-mediated autophagy), in driving cells toward ferroptotic death motivated us to explore the functional interactions between metabolism, immunity, and cell death. Here, we describe types of selective autophagy and discuss the regulatory mechanisms and signaling pathways of autc;: hagy-dependent ferroptosis. We also summarize chemical modulo tors that are currently available for triggering or blocking autophagy-dependent ferroptosis and that may be developed for therapeutic interventions in human diseases.