Maxing Loushi Decoction alleviates COPD by targeting the PD-1/PD-L1 pathway: restoring Th17/Treg balance and inhibiting ferroptosis

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder driven by immune dysregulation and ferroptosis, with limited therapies addressing its underlying pathogenesis. Maxing Loushi Decoction (MXLS), a modified traditional Chinese medicine (TCM) formula, has shown clinical efficacy in COPD, but its molecular mechanisms remain unclear. This study aimed to explore the therapeutic mechanisms of MXLS in COPD. A COPD mouse model was established via cigarette smoke (CS) exposure combined with lipopolysaccharide (LPS) administration. MXLS was intragastrically administered, with dexamethasone (DX) as a positive control. Lung function, histopathological changes, CD4+ T cell subsets, PD-1/PD-L1 expression, and ferroptosis-related indicators were evaluated. In vitro experiments included Th17 polarization induction, CD4+ T cell-MLE-12 cell co-culture, and intervention with anti-PD-1 antibody. MXLS significantly improved lung function, alleviated airway inflammation and alveolar destruction in cigarette smoke- and LPS-induced COPD mice, with efficacy comparable to DX. MXLS downregulated PD-1/PD-L1 expression in lung tissue and CD4+ T cells, restored Th17/Treg balance by reducing Th17 cell frequency and increasing Treg cell proportion, and inhibited ferroptosis by reducing Fe2+ accumulation, restoring GSH/SOD levels, and upregulating ferroptosis-related protective proteins (GPX4, SLC7A11, FTH1). In vitro, MXLS-modulated CD4+ T cells alleviated epithelial cell inflammation and ferroptosis, and combining MXLS with anti-PD-1 antibody enhanced these effects. MXLS may exerts therapeutic effects in a cigarette smoke- and LPS-induced COPD model, at least in part through modulation of the PD-1/PD-L1 pathway, concurrently restoring Th17/Treg immune homeostasis and inhibiting ferroptosis. This study provides a scientific basis for MXLS as a potential COPD therapy. MXLS alleviates cigarette smoke- and LPS-induced COPD by targeting the PD-1/PD-L1 pathway, regulating immune dysregulation and ferroptosis. MXLS can both restore Th17/Treg immune balance and inhibit lung epithelial ferroptosis, thereby alleviating COPD-induced lung injury. MXLS exhibits efficacy comparable to dexamethasone with potential advantages in safety, offering a promising alternative for glucocorticoid-intolerant COPD patients.