Revisiting Tumors and the Cardiovascular System: Mechanistic Intersections and Divergences in Ferroptosis

Figure 3

Autophagy exerts vital effects on ferroptosis via multiple mechanisms. (a) Ferritinophagy, the NCOA4-dependent degradation of ferritin, accumulates ferrous iron to induce ferroptosis. (b) Mitophagy, the degradation of impaired mitochondria via the gathering of PINK1 and PRKN as well as the transport of cargo receptors, produces “killing ROS” to advance ferroptosis. (c) CMA degrades its substrate GPX4 through the interaction between Lamp-2a located in lysosomes and the GPX4-HSC70-HSP90 trimer, resulting in ferroptosis. (d) Lipophagy, the RAB7A- and ATG5-dependent degradation of lipid droplets, increases the level of fatty acids. Clockophagy, the SQSTM1-dependent degradation of ARNTL, changes the status of fatty acid oxidation and lipid droplet storage by decreasing HIF1A after increasing EGLN2. Both lipophagy and clockophagy trigger abnormal lipid metabolism to regulate ferroptosis. Relevant abbreviations: NCOA4: nuclear receptor coactivator 4; PINK1: PTEN-induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; CMA: chaperone-mediated autophagy; HSC70: heat shock cognate 70; HSP90: heat shock protein 90; Lamp-2a: lysosome-associated membrane protein type 2a; RAB7A: a member of the RAS oncogene family; ATG5: autophagy-related 5; ARNTL: aryl hydrocarbon receptor nuclear translocator-like protein 1; SQSTM1: sequestosome 1; EGLN2: egl nine homolog 2; HIF1A: hypoxia-inducible factor 1 subunit alpha.

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