Activation of Nrf2 signaling pathway by Tectoridin protects against ferroptosis in particulate matter-induced lung injury.

Abstract

Our previous research showed that ferroptosis plays a crucial role in the pathophysiology of PM2.5-induced lung injury. The present study aimed to investigate the protective role of the Nrf2 signaling pathway and its bioactive molecule tectoridin (Tec) in PM2.5-induced lung injury by regulating ferroptosis. We examined the regulatory effect of Nrf2 on ferroptosis in PM2.5-induced lung injury and Beas-2b cells using Nrf2-knockout (KO) mice and Nrf2 siRNA transfection. Moreover, the effect and underlying mechanism of Tec on PM2.5-induced lung injury were evaluated in vitro and in vivo. As anticipated, Nrf2 deletion increased iron accumulation and ferroptosis-related protein expression in vivo and vitro, further exacerbating lung injury and cell death in response to PM2.5 exposure. Tec significantly activated Nrf2 target genes and ameliorated cell death caused by PM2.5. In addition, Tec prevented lipid peroxidation, iron accumulation, and ferroptosis in vitro, but in siNrf2-treated cells, these effects almost disappeared. In addition, Tec effectively mitigated PM2.5-induced respiratory system damage, as evaluated by HE, PAS, and inflammatory factors. Tec also augmented the antioxidative Nrf2 signaling pathway and prevented changes in ferroptosis-related morphological and biochemical indicators, including MDA levels, GSH depletion and GPX4 and xCT downregulation, in PM2.5-induced lung injury. However, the effects of Tec on ferroptosis and respiratory injury nearly vanished in Nrf2-KO mice. Our data proposed the protective effect of Nrf2 activation on PM2.5-induced lung injury by inhibiting ferroptosis-mediated lipid peroxidation and highlight the potential of Tec as a PM2.5-induced lung injury treatment.