Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

TLDR

Seawater drowning causes acute lung injury through severe oxidative stress, and ferroptosis—a ROS‑driven, nonapoptotic cell death—has been implicated, while Nrf2 is known to suppress ferroptosis and preserve redox homeostasis. We tested whether activating Nrf2 attenuates seawater drowning‑induced ALI by inhibiting ferroptosis. We used the Nrf2 agonist dimethyl fumarate, the inhibitor ML385, Nrf2‑knockout mice, and the ferroptosis inhibitor ferrostatin‑1 to examine Nrf2’s role and underlying mechanisms in seawater drowning‑induced ALI. Activation of Nrf2 by dimethyl fumarate enhanced cell viability, lowered ROS and lipid peroxidation, preserved glutathione and mitochondrial integrity, and upregulated FTH1/GPX4, whereas inhibition or loss of Nrf2 exacerbated cell death and lung injury, demonstrating that Nrf2 suppresses ferroptosis and mitigates seawater drowning‑induced ALI, highlighting ferroptosis inhibition as a novel therapeutic strategy.

Abstract

Abstract Background Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. Methods we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. Results Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. Conclusions These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.