The Therapeutic Effect and Mechanism of Vismodegib on COPD : Focusing on NETs and Macrophage Polarization

ABSTRACT The Hedgehog pathway may be involved in chronic obstructive pulmonary disease (COPD). Its inhibitor, Vismodegib, has therapeutic potential, but the underlying mechanisms require further investigation. A COPD mouse model was established using lipopolysaccharide (LPS) and cigarette smoke exposure, with concurrent Vismodegib intervention. Assessments included histopathology, pulmonary function, inflammatory cytokines, neutrophil extracellular traps (NETs) markers, macrophage polarization, and integrated transcriptomic and gut microbiota (16S rRNA) analysis. The results show that Vismodegib alleviated lung injury and fibrosis, regulated the respiratory rate, reduced the levels of pro‐inflammatory cytokines such as interleukin (IL)‐6 (IL‐6), IL‐1β, and tumor necrosis factor‐α (TNF‐α), promoted a phenotypic shift from M1 to M2 macrophage polarization, and suppressed NETs formation, as demonstrated by decreased levels of neutrophil elastase (NE), citrullinated histone H3 (Cit‐H3), myeloperoxidase (MPO), and Cit‐H3 + Ly6G + cells. Multi‐omics analysis revealed enrichment of the IL‐17 signaling pathway and increased gut microbial abundance of Bacteroidaceae and Tannerellaceae . Vismodegib may alleviate inflammation and tissue damage in COPD by inhibiting NETs‐mediated M1 polarization of macrophages. This study is the first to propose the targeting of NET‐driven macrophage polarization via Hedgehog inhibition as a novel therapeutic strategy for COPD, providing a new mechanistic framework for drug repurposing.