Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice

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 fer-roptosis. 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 fer-roptosis, thereby demonstrating that SIRT6 holds great promise as a therapeutic target for ALI. targeting of ferroptosis has been suggested as a potential treatment strategy for ALI; although, further research is needed to fully elucidate the regulatory mechanism of ferroptosis in ALI [5,6].Ferroptosis is characterized by the accumulation of iron and reactive oxygen species (ROS), which induces the production of lipid hydroperoxides (LOOHs) and cell death [2,7]. Glutathione peroxidase 4 (GPX4) exerts a negative effect on the regulation of ferroptosis by preventing the accumulation of lipid peroxides in a glutathione (GSH)-dependent manner. In addition, the cystine/glutamate transporter system (xc-system) present in the cell membrane plays a crucial role in GSH production. The function of xc-system is to transfer cysteine into cells, where it is an important component for GSH production. Several studies suggest that p53 protein plays an important role in the regulation of ferroptosis and is involved in multiple diseases [8,9]. Recent studies have demonstrated that p53 regulates ferroptosis by targeting SLC7A11, a key component of the xc-system [9,10].Sirtuin 6 (SIRT6), a member of the sirtuin family of NAD (+)-dependent deacetylases, includes seven members (SIRT1 to SIRT7) [11,12]. SIRT6 has been shown to exert protective effects in various diseases [13,14]; however, the role of SIRT6 in ALI remains unclear. Recent studies have demonstrated that SIRT6 exerts its biological effects by regulating p53-mediated ferroptosis [15,16]. In the present study, we investigate the protective effect of SIRT6 against LPS-induced ALI by the regulation of p53-mediated ferroptosis.