Ferrostatin-1 and 3-Methyladenine Ameliorate Ferroptosis in OVA-Induced Asthma Model and in IL-13-Challenged BEAS-2B Cells

Abstract

Ferroptosis was reported to be involved in the occurrence and development of asthma. However, the potential mechanism underlying the role of ferroptosis in asthma remains unclear. In this study, we established the mouse asthma model following the ovalbumin (OVA) method in C57BL/6 mice and the cell model with IL-13 induction in bronchial epithelial cells (BEAS-2B cells). Treatment of ferrostatin-1 (Ferr-1) and 3-methyladenine (3-MA) decreased iron deposition in IL-13-induced BEAS-2B cells and lung tissues of asthma mice, opposite to that in bronchoalveolar lavage fluid (BALF). Meanwhile, excessive lipid peroxidation asthma model in vivo and in vitro was alleviated by Ferr-1 or 3-MA treatment. In addition, Ferr-1 and 3-MA inhibited the expression of LC-3 in these cells and lung tissues of mice. Moreover, Ferr-1 and 3-MA also suppressed the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and oxidative stress factors (ROS and MDA), while promoting the level of SOD, in vivo and in vitro. Furthermore, application of Ferr-1 exhibited a greater inhibitory effect on iron release and lipid peroxidation in IL-13-induced BEAS-2B cells and asthma mice than 3-MA, accompanied with a weaker effect on ferritinophagy than 3-MA. Collectively, Ferr-1 and 3-MA ameliorated asthma in vivo and in vitro through inhibiting ferroptosis, providing a new strategy for the clinical treatment of asthma.

Multifaceted Roles of Ferroptosis in Lung Diseases

“…These results reveal the correlation between ferroptosis and the pathobiologic pathway of asthma and the possibility of targeted inhibition of ferroptosis. Ferrostatin-1 and deferoxamine are introduced to reduce sensitivity to ferroptosis (Wenzel et al, 2017;Yang and Shang, 2022); otherwise, the 15LOX1/PEBP1 pathway is under investigation as a novel asthma therapeutic target to regulate the ferroptotic cell death (Zhao et al, 2011). On the other hand, 3-methyladenine was proven to ameliorate ferroptosis in an ovalbumin (OVA)-induced asthma model by suppressing the production of ROS and inflammatory cytokines, while upregulating superoxide dismutase (SOD) (Yang and Shang, 2022).…”

“…Ferrostatin-1 and deferoxamine are introduced to reduce sensitivity to ferroptosis (Wenzel et al, 2017;Yang and Shang, 2022); otherwise, the 15LOX1/PEBP1 pathway is under investigation as a novel asthma therapeutic target to regulate the ferroptotic cell death (Zhao et al, 2011). On the other hand, 3-methyladenine was proven to ameliorate ferroptosis in an ovalbumin (OVA)-induced asthma model by suppressing the production of ROS and inflammatory cytokines, while upregulating superoxide dismutase (SOD) (Yang and Shang, 2022). In addition, acupuncture was reported to be effective in treating asthma by reducing solute carrier family 3 member 2 (SLC3A2) and ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3) expression, oxidative stress, and inflammatory cytokine levels and was recently connected with the manipulation of ferroptosis (Tang et al, 2021c).…”

Involvement of Ferroptosis in Diabetes-Induced Liver Pathology

“…Fer-1 is one of the most potent ferroptosis inhibitors that exhibits high efficacy as radical-trapping antioxidants, with a particularly high potency in phospholipid bilayer membranes when compared to other antioxidants [ 19 ]. Its metabolic actions in vivo were extensively evidenced, and it is a well-established pharmacological tool for verification of ferroptosis [ 11 , 12 , 18 , 20 , 21 , 22 , 23 , 24 ].…”

Treatment with the Ferroptosis Inhibitor Ferrostatin-1 Attenuates Noise-Induced Hearing Loss by Suppressing Ferroptosis and Apoptosis

“…Ferrostatin-1 (Fer-1), a synthetic antioxidant, is widely recognized for its ability to inhibit ferroptosis [24][25][26]. Ferroptosis, which was first proposed in 2012 by Dixon [27], has been identified as a new mode of cell death that is distinct from apoptosis and characterized by the deposition of iron and lipid peroxidation.…”