Abstract Objective: Previously, we demonstrated that polydatin (PD) protected against acute lung injury (ALI) by upregulation of mitophagy; however, the mechanism remains unclear. In the present study, we aimed to determine whether PD facilitates mitophagy by downregulating p53 and then alleviates ferroptosis in ALI. Materials and Methods: Lipopolysaccharide (LPS) was administered intratracheally to the mice to induce ALI. ALI was induced by stimulating mouse lung epithelial cell line-12 (MLE-12) cells with 5 μg/mL LPS for 12 h in vitro . Results: We found that the downregulation of mitophagy by silencing Prkn (Parkin) exacerbated LPS-induced ferroptosis, suggesting the protective effect of Parkin-dependent mitophagy prevents LPS-induced ferroptosis. Furthermore, PD treatment alleviated LPS-induced ferroptosis; however, the protective effect of PD was attenuated by mitophagy inhibition. We previously reported that p53 promotes ferroptosis in ALI via an as-yet-unknown mechanism. Herein, p53 was observed to interact with Parkin to prevent its translocation into mitochondria, thereby decreasing mitophagy in ALI. Moreover, upregulating p53 exacerbated LPS-induced ferroptosis, which was rescued by upregulation of mitophagy, indicating that p53 facilitates ferroptosis by depressing mitophagy. In the present study, we found that PD treatment prevented LPS-induced upregulation of p53. Moreover, overexpression of p53 inhibited PD-mediated upregulation of mitophagy and its protective effect against ferroptosis. Interestingly, upregulation of mitophagy rescued the reduced protective effect of PD against ferroptosis due to overexpression of p53. Conclusions: This study reveals that PD treatment prevents LPS-induced ferroptosis by upregulation of Parkin-dependent mitophagy in ALI. Additionally, p53 interacts with Parkin to facilitate ferroptosis by depressing mitophagy. We further found that PD enhances Parkin-dependent mitophagy by downregulating p53.
Cao et al. (Wed,) studied this question.