Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice
Yuanyuan Cao,
Tian Peng,
Chenmu Ai,
Zhiwang Li,
Xiaobao Lei,
Guicheng Li,
Tao Li,
Xiang Wang,
Shumin Cai
Affiliations
Yuanyuan Cao
Department of Critical Care Medicine, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, PR China; Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Tian Peng
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Chenmu Ai
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Zhiwang Li
Department of Anesthesiology, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Xiaobao Lei
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Guicheng Li
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Tao Li
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China
Xiang Wang
Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The First Affiliated Hospital of Xiangnan University, Xiangnan University, Chenzhou, 423000, PR China; Corresponding author. Department of Critical Care Medicine, The First People's Hospital of Chenzhou, The first affiliated Hospital of Xiangnan University, Xiangnan University, No.102 Luojiajing, Chenzhou, 423000, Hunan Province, PR China.
Shumin Cai
Department of Critical Care Medicine, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, PR China; Corresponding author. Department of Critical Care Medicine, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, NO. 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong Province, PR China.
Although studies have shown that protein 53 (p53)-mediated ferroptosis is involved in acute lung injury (ALI), the mechanism of its regulation remains unclear. The protective effects of Sirtuin 6 (SIRT6), a histone deacetylase, have been demonstrated in multiple diseases; however, further studies are needed to elucidate the role of SIRT6 in ALI. In the present study, we hypothesize that SIRT6 protects against lipopolysaccharide (LPS)-induced ALI by regulating p53-mediated ferroptosis. We observed that the inhibition of ferroptosis prevented LPS-induced ALI. The knockout of p53 blocked LPS-induced ferroptosis and ALI, suggesting that p53 facilitated ALI by promoting ferroptosis. In addition, the inhibition of SIRT6 aggravated LPS-induced ferroptosis and ALI, while the depression of ferroptosis blocked the exacerbation of lung injury induced by SIRT6 inhibition. The results suggest that SIRT6 protects against ALI by regulating ferroptosis. Furthermore, the inhibition of SIRT6 reinforced the p53 acetylation and the deletion of p53 rescued the exacerbation of ferroptosis induced by SIRT6 inhibition. The findings indicate that SIRT6 regulates the acetylation of p53 and prevents p53-mediated ferroptosis. In conclusion, our results indicate that SIRT6 protects against LPS-induced ALI by regulating p53-mediated ferroptosis, thereby demonstrating that SIRT6 holds great promise as a therapeutic target for ALI.
