Qibai Pingfei Capsule ameliorates NK‑cell dysfunction in COPD: insights from single‑cell sequencing in a randomized multicenter double‑blinded placebo‑controlled trial

BACKGROUND: Chronic inflammation in chronic obstructive pulmonary disease (COPD) arises from prolonged interactions among immune cells, functional cells, and inflammatory cytokines. The Qibai Pingfei Capsule (QBPF), a traditional Chinese medicine (TCM), has been utilized clinically for over two decades to treat COPD. However, robust evidence is required to validate its clinical effectiveness. Single‐cell RNA sequencing (scRNA‐seq) technology offers comprehensive insights into the immune‐inflammatory microenvironment of COPD at the single‐cell level, providing valuable strategies for integrating TCM into COPD management. PURPOSE: To clarify the mechanism of QBPF in treating COPD through scRNA‐seq. METHODS: A randomized, double‐blind, placebo‐controlled, multicenter study performed to investigate the QBPF efficacy in COPD patients. PBMCs from these patients were subjected to scRNA‐seq, and lung tissue scRNA‐seq data were obtained from the public database (GEO: GSE162610). The regulatory mechanism of QBPF was confirmed using a COPD rat model. RESULTS: Acute exacerbation frequency was significantly decreased (p = 0.042), and CAT scores improved (p = 0.008) following QBPF treatment. Nevertheless, no significant changes were recorded in lung function, the 6‐minute walk test (6MWT), or the mMRC scale. Within the QBPF group, the 6MWT (p < 0.01) and FEV₁/FVC% (p < 0.01) significantly improved from baseline to 3 months. ScRNA‐seq confirmed immune dysfunction, especially the depleted NK cells and impaired activation. QBPF altered the expression of functional markers in NK cells of COPD patients, and animal studies confirmed that QBPF enhanced NK cell activity by modulating the expression of hepatitis A virus cellular receptor 2 (HAVCR2) and killer cell lectin‐like receptor C2 (KLRC2). Additionally, scRNA‐seq analysis revealed impaired immune function in COPD patients, specifically NK cell exhaustion and dysfunction. CONCLUSION: These findings demonstrated that QBPF can ameliorate and alleviate COPD symptoms, and its therapeutic effects have been linked to its potential to modulate NK cell function. This study provides some evidence that QBPF can improve NK cell activity in COPD.