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Research Article | Open Access | Just Accepted

Targeted inhibition NCOA4-mediated ferritinophagy limits ferroptosis to ameliorate alcohol-induced liver injury in vivo and in vitro

Yanan ZhaoBin LiJiang LiuFei YuLei ChenHui Teng()

College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, Guangdong 524000, People’s Republic of China;

Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Zhanjiang, Guangdong 524000, People’s Republic of China;

Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang, Guangdong 524000, People’s Republic of China;

Guangdong Provincial Engineering Technology Research Center of Seafood, Zhanjiang, Guangdong 524000, People’s Republic of China;

Key Laboratory of Advanced Processing of Aquatic Product of Guangdong Higher Education Institution, Zhanjiang, Guangdong 524000, People’s Republic of China.

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Abstract

Alcoholic liver injury (ALD) is a serious liver disease resulting from prolonged and excessive alcohol consumption, with significant morbidity and mortality and closely relate to iron accumulation and ferroptosis. Ferritinophagy is the process of autophagic degradation of ferritin and results in labile iron accumulation and ferroptosis. However, whether ferritinophagy involves in alcohol-induced liver injury and ferroptosis remains unexplored. Here, we demonstrated the involvement of ferroptosis in alcohol-induced liver injury by modulating nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Utilizing both in vivo and in vitro models, we observed activation of autophagy and ferroptosis following alcohol administration. Intriguingly, we found that alcohol-induced ferroptosis is autophagy-dependent, because autophagy inhibitor 3-MA (30 mg/kg bw. in vivo,1 mM in vitro, respectively) profoundly mitigated alcohol-induced ferroptosis. We further demonstrated that alcohol-induced ferritinophagy was derived by iron overload, by showing that iron chelator DFO (100 mg/kg bw. in vivo, 10 μM in vitro, respectively) can abolish alcohol-induced ferritinophagy and ferroptosis. Moreover, we observed an upregulation of NCOA4 expression, and knockdown of NCOA4 significantly reversed alcohol-induced disturbances in iron metabolism and subsequently blocking ferroptosis. Our findings suggest a connection between ferritinophagy and alcohol-induced ferroptosis in mouse liver and HepG2 cells, highlighting NCOA4-mediated ferritinophagy as a novel mechanism of alcohol-induced liver injury. This study enhances our understanding of the molecular mechanisms underlying alcohol-induced liver injury, and targeting ferritinophagy may provide new strategies for preventing or treating ALD.

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Food Science and Human Wellness
Cite this article:
Zhao Y, Li B, Liu J, et al. Targeted inhibition NCOA4-mediated ferritinophagy limits ferroptosis to ameliorate alcohol-induced liver injury in vivo and in vitro. Food Science and Human Wellness, 2024, https://doi.org/10.26599/FSHW.2024.9250313
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