Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis
Aimin Wu,
Bin Feng,
Jie Yu,
Lijun Yan,
Lianqiang Che,
Yong Zhuo,
Yuheng Luo,
Bing Yu,
De Wu,
Daiwen Chen
Affiliations
Aimin Wu
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
Bin Feng
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
Jie Yu
Key Laboratory for Animal Disease-resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
Lijun Yan
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
Lianqiang Che
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
Yong Zhuo
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
Yuheng Luo
Key Laboratory for Animal Disease-resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China
Bing Yu
Key Laboratory for Animal Disease-resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China; Corresponding author.
De Wu
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Corresponding author.
Daiwen Chen
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Chengdu, China; Corresponding author. Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China.
Ferroptosis plays a role in several diseases such as iron overload-induced liver diseases. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. Numerous antioxidants have been identified to control ferroptosis but the cell-autonomous mechanisms responsible for regulating ferroptosis remain elusive. In the present study, we found that iron overload promoted ferroptosis in hepatocytes by excessively inducing HO-1 expression, which contributed to the progression of liver injury and fibrosis, accompanied by the upregulation of the FGF21 protein level in vitro and in vivo. Interestingly, both recombinant FGF21 and Fgf21 overexpression significantly protected against iron overload-induced hepatocytes mitochondria damage, liver injury and fibrosis by inhibiting ferroptosis. In contrast, the loss of FGF21 aggravated iron overload-induced ferroptosis. Notably, FGF21-induced HO-1 inhibition (via the promotion of HO-1 ubiquitination and degradation) and NRF2 activation provide a mechanistic explanation for this phenomenon. Taken together, we identified FGF21 as a novel ferroptosis suppressor. Thus, FGF21 activation may provide an effective strategy for the potential treatment of iron overload-induced ferroptosis-related diseases, such as hereditary haemochromatosis (HH).
