Scutellarein alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis by chelating iron and interacting with arachidonate 15‐lipoxygenase

Abstract

Ferroptosis, an iron‐dependent cell death characterized by lethal lipid peroxidation, is involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, ferroptosis inhibition represents an attractive strategy for COPD therapy. Herein, we identified natural flavonoid scutellarein as a potent ferroptosis inhibitor for the first time, and characterized its underlying mechanisms for inhibition of ferroptosis and COPD. In vitro, the anti‐ferroptotic activity of scutellarein was investigated through CCK8, real‐time quantitative polymerase chain reaction (RT‐qPCR), Western blotting, flow cytometry, and transmission electron microscope (TEM). In vivo, COPD was induced by lipopolysaccharide (LPS)/cigarette smoke (CS) and assessed by changes in histopathological, inflammatory, and ferroptotic markers. The mechanisms were investigated by RNA‐sequencing (RNA‐seq), electrospray ionization mass spectra (ESI‐MS), local surface plasmon resonance (LSPR), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular dynamics. Our results showed that scutellarein significantly inhibited Ras‐selective lethal small molecule (RSL)‐3‐induced ferroptosis and mitochondria injury in BEAS‐2B cells, and ameliorated LPS/CS‐induced COPD in mice. Furthermore, scutellarein also repressed RSL‐3‐ or LPS/CS‐induced lipid peroxidation, GPX4 down‐regulation, and overactivation of Nrf2/HO‐1 and JNK/p38 pathways. Mechanistically, scutellarein inhibited RSL‐3‐ or LPS/CS‐induced Fe2+ elevation through directly chelating Fe2+. Moreover, scutellarein bound to the lipid peroxidizing enzyme arachidonate 15‐lipoxygenase (ALOX15), which resulted in an unstable state of the catalysis‐related Fe2+ chelating cluster. Additionally, ALOX15 overexpression partially abolished scutellarein‐mediated anti‐ferroptotic activity. Our findings revealed that scutellarein alleviated COPD by inhibiting ferroptosis via directly chelating Fe2+ and interacting with ALOX15, and also highlighted scutellarein as a candidate for the treatment of COPD and other ferroptosis‐related diseases.

Recent advances in the potential effects of natural products from traditional Chinese medicine against respiratory diseases targeting ferroptosis

“…Liu et al found that scutellarin prevented RSL3-induced ferroptosis and damage in BEAS-2B cells and alleviated LPS/CS-induced COPD in mice. Mechanistically, scutellarein directly chelates Fe 2+ and interacts with ALOX15 to reduce lipid peroxidation, reverse GPX4 downregulation, and block Nrf2/HO-1 and JNK/ p38 pathway overactivation [169]. According to existing research, the main effect of this intervention is the suppression of ferroptosis, leading to enhanced mitigation of chronic inflammation and airway constriction in individuals with COPD.…”

Scutellarein alleviates osteoarthritis progression through the PI3K/Akt/NF‐kappaB signaling pathway: In vitro and in vivo studies

“…These observations, consistent with our in vitro experimental outcomes, strongly suggest the therapeutic potential of Scu in the treatment of OA. After consulting other studies, we determined that 20 mg/kg was the ideal Scu dosage, upon which we better observed the effect of Scu on OA (Liu et al, 2021;Liu, Zhang, et al, 2023). Given the significance of the PI3K/ Akt pathway in OA, we consider the discovery of novel inhibitors of this pathway as targeted medicines to be promising.…”

Analysis of network expression and immune infiltration of disulfidptosis‐related genes in chronic obstructive pulmonary disease

“…Cell death processes such as apoptosis, necrosis, ferroptosis, and pyroptosis are believed to be associated with the progression of COPD. [7][8][9][10] These processes typically interact within a complex network, contributing to the sustained inflammatory state observed in COPD patients. A comprehensive understanding of the specific roles of these cell death pathways and how they interplay in the pathophysiology of COPD is crucial for comprehension of this disease.…”