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Lipid storage and lipophagy regulates ferroptosis

Bai, Yuansong, Meng, Lingjun, Han, Leng, Jia, Yuanyuan, Zhao, Yanan, Gao, Huan, Kang, Rui, Wang, Xiaofeng, Tang, Daolin, Dai, Enyong
Biochemical and biophysical research communications 2019 v.508 no.4 pp. 997-1003
antioxidants, cell death, droplets, hepatocytes, humans, inflammation, lipid metabolism, lipid peroxidation, lipids, mice
The synthesis, storage, and degradation of lipids are highly regulated processes. Impaired lipid metabolism is implicated in inflammation and cell death. Although ferroptosis is a recently described form of regulated cell death driven by lipid peroxidation, the impact of lipid droplets on ferroptosis remains unidentified. Here, we demonstrate that lipophagy, the autophagic degradation of intracellular lipid droplets, promotes RSL3-induced ferroptotic cell death in hepatocytes. Lipid droplet accumulation is increased at the early stage but decreased at the late stage of ferroptosis in mouse or human hepatocytes. Importantly, either genetically enhancing TPD52-dependent lipid storage or blocking ATG5-and RAB7A-dependent lipid degradation prevents RSL3-induced lipid peroxidation and subsequent ferroptosis in vitro and in vivo. These studies support an antioxidant role for lipid droplets in cell death and suggest novel strategies for the inhibition of ferroptosis by targeting the lipophagy pathway.