Affiliation:
1. Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
2. Department of Intensive Care Unit, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
Abstract
ABSTRACT
The molecular mechanism for nobiletin's protective effect against heatstroke-induced acute lung injury (HS-ALI) remains largely unknown. Previous research has demonstrated that ferroptosis is an important pathogenic event in HS-ALI. Nobiletin is a natural polymethoxylated flavonoid. Herein, we investigated the potential contribution of nobiletin to HS-ALI by inhibiting ferroptosis. Heat stress was used to induce HS-ALI in mice, and mouse lung epithelial-12 (MLE-12) cells were stimulated by heat stress in vitro. Nobiletin was administrated by gavage for 2 h before HS induction. Biochemical kits, immunofluorescence staining, and western blotting were performed on the markers of ferroptosis. Our results showed that nobiletin administration significantly attenuated HS-induced lung injury and ferroptosis. Moreover, nobiletin pretreatment significantly reversed HS-induced p53 upregulation in vivo and in vitro. Pretreatment with a p53 agonist, tenovin-6, partly abolished the protective effect of nobiletin in mice with HS-ALI. Meanwhile, p53 knockdown significantly increased GPX4 and SLC7A11 expression levels compared with the HS group in HS-induced MLE-12 cells. Subsequently, nobiletin ameliorated HS-induced MLE-12 cells ferroptosis by activating the SLC7A11/GPX4 pathway, whereas p53 overexpression effectively abolished the protective effect of nobiletin. Taken together, our findings reveal that nobiletin attenuates HS-ALI by inhibiting ferroptosis through the p53/SLC7A11 pathway, indicating it to be a potential therapeutic agent for HS-ALI prevention and treatment.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Critical Care and Intensive Care Medicine,Emergency Medicine