Notoginsenoside R1 modulates the ATF4-CHOP-Bcl2 signaling pathway to alleviate mitochondrial stress damage and apoptosis in asthmatic airway epithelial cells.

Objective: To investigate whether Notoginsenoside R1 (NG-R1) improves mitochondrial homeostasis by targeting the integrin signaling response (ISR) core transcription factor ATF4, thereby alleviating damage and apoptosis in asthma airway epithelial cells. Methods: House dust mites (HDM) were used to establish an Results: ATF4 expression was significantly elevated in lung tissue from asthmatic mice and in HDM-stimulated BEAS-2B cells, and was positively correlated with increased epithelial cell apoptosis and reduced migration and repair capacity. ATF4 knockdown alleviates HDM-induced increases in mitochondrial reactive oxygen species (ROS), decreases in membrane potential, mitochondrial ultrastructural damage, and disbalance in fission/fusion (downregulation of p-Drp1/Drp1 and upregulation of Mfn2 and ATP5F1A) via the ATF4-CHOP-Bcl2 signaling pathway, thereby inhibiting apoptosis. NG-R1 intervention significantly reduced airway hyperresponsiveness, total inflammatory cell counts in BALF, and levels of Th2 cytokines (IL-4, IL-13, IL-33) in asthmatic mice, and alleviated pulmonary inflammatory infiltration. Molecular docking and Conclusion: NG-R1 may regulate the ATF4-CHOP-Bcl2 signaling pathway by specifically binding to and downregulating ATF4, thereby alleviating mitochondrial stress-induced damage, inhibiting airway epithelial cell apoptosis, and promoting epithelial repair, suggesting that NG-R1 is a potential candidate drug for targeted asthma therapy.