Ginsenoside Rg1 improves cigarette smoke-induced ferroptosis in COPD by regulating PERK/ATF4 axis to inhibit endoplasmic reticulum stress.

Background: Ferroptosis plays a key role in the development of chronic obstructive pulmonary disease (COPD). Whether ginsenoside Rg1 improves cigarette smoke-induced COPD or whether ginsenoside Rg1 improves COPD by inhibiting ferroptosis remains unknown.

Methods: BEAS-2B cells were exposed to cigarette solution (CSE) for 24 h and treated with ginsenoside Rg1, the ferroptosis inhibitor Fer-1, and the PERK inhibitor GSK. Cell viability, endoplasmic reticulum stress, mitochondrial morphology, membrane potential, reactive oxygen species (ROS), iron levels, and the expression of related proteins were detected using corresponding methods. A COPD mouse model was constructed using cigarette smoke (CS). Ginsenoside Rg1 and GSK were administered via tube feeding 15 days after successful modeling. Mouse lung tissues were evaluated by HE staining. The expression of inflammatory markers, ROS, iron content, and related proteins was detected using corresponding methods.

Results: The results demonstrated that in the CSE-exposed BEAS-2B cell model and CS-induced mouse COPD model, the expression levels of endoplasmic reticulum stress (ERS)-related factors such as GRP78 were increased, while those of the antioxidant markers GPX4 and GSH were significantly decreased. Ginsenoside Rg1 improved emphysema and inflammation by inhibiting ferroptosis in vivo and in vitro. Using a PERK inhibitor, we found that ginsenoside Rg1 inhibited ferroptosis in vivo and in vitro by regulating ERS.

Conclusion: This study showed that ginsenoside Rg1 alleviates cigarette smoke-induced COPD by regulating the PERK/ATF4 axis to inhibit ERS and ferroptosis.