NLBK alleviates airway remodeling in COPD by inhibiting RXRA-mediated transcription of PLA2G2A.

OBJECTIVES: Nourishing lung benefiting kidney granule (NLBK) is used to treat chronic obstructive pulmonary disease (COPD). However, the molecular mechanism underlying its therapeutic effect is still unclear. In this study, we elucidated the molecular mechanism by which NLBK alleviates airway reorganization in COPD. METHODS: We investigated the function of NLBK in regulating inflammatory reactions and endoplasmic reticulum stress (ERS) in mice with COPD. Through bioinformatics and network pharmacology analysis, we identified the main components and targets: Zhebeiresinol-nuclear receptors such as Retinol X receptor A (RXRA) and Phospholipase A2, group IIA (PLA2G2A). A rescue experiment was performed to confirm the relationship between Zhebeiresinol and PLA2G2A in alleviating COPD symptoms. Moreover, by conducting a series of experiments, we determined the transcriptional regulation of RXRA on PLA2G2A. RESULTS: NLBK significantly inhibited cigarette smoke exposure-induced inflammatory response, lung function injury, and ERS in COPD mice. Zhebeiresinol acted as an active ingredient of NLBK, which was found to mitigate the inflammatory response, lung function injury, and ERS in COPD mice through the silencing of PLA2G2A, the specific target of NLBK. Zhebeiresinol repressed the phosphorylation of RXRA and entry into the nucleus, which efficiently suppressed the transcription of PLA2G2A. CONCLUSIONS: NLBK can alleviate airway remodeling in COPD through the RXRA-PLA2G2A axis, providing a new mechanistic basis for the clinical application of NLBK.