Work

Bufei Huoxue Granules target the mitophagy–senescence–inflammation axis to alleviate cigarette smoke-induced COPD: integrating network pharmacology and experimental validation

Year: 2025

Type: article

Abstract: Aim of the study This study sought to elucidate the potential mechanisms of Bufei Huoxue Granules (BFHXG) in the treatment of chronic obstructive pulmonary disease (COPD), specifically examining its features related to senescence modulation and the associated molecular pathways. Materials and methods The therapeutic efficacy of BFHXG was evaluated in a COPD mouse model induced by chronic cigarette smoke (CS) exposure. Comprehensive analytical approaches, including ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), network pharmacology analysis, and molecular docking simulations, were used to identify bioactive compounds and elucidate the underlying mechanisms. Pulmonary pathophysiology was evaluated using lung function tests, histopathological assessment (H&E staining), ultrastructural examination via transmission electron microscopy (TEM), immunofluorescence co-localization assays, and Western blot quantification of inflammatory mediators, senescence biomarkers, and mitophagy regulators. Results UPLC-Q-TOF/MS identified 56 components in BFHXG, with 43 bioactive ingredients corresponding to 582 potential targets through network pharmacology analysis, indicating an association with mitophagy, cellular senescence, and inflammatory responses. Molecular docking simulations demonstrated strong binding interactions between BFHXG components and mitophagy regulators (PINK1/Parkin), suggesting that mitophagy activation serves as an anti-senescence axis. BFHXG treatment markedly alleviated lung function impairment, attenuated emphysema, and reduced lung histological damage in COPD mice. Concurrently, BFHXG downregulated the expression of senescence-associated markers [e.g., senescence-associated β-galactosidase (SA-β-gal), p16, and p21], and reduced the expression of senescence-associated secretory phenotype (SASP) factors (e.g., IL-1β, IL-6, and MMP-9) in lung tissues. Its efficacy was comparable to or even superior to that of the positive control drug roflumilast (ROF). Furthermore, BFHXG increased the LC3-II/LC3-I ratio and enhanced PINK1/Parkin expression, exhibiting effects similar to those of the mitophagy activator Urolithin A (UroA). Mitochondrial Division Inhibitor 1 (Mdivi-1) negated the effects induced by BFHXG, specifically by inhibiting LC3-II conversion and PINK1/Parkin expression, promoting p62 protein accumulation, and eventually upregulating the expression of senescence markers. Conclusion BFHXG attenuates COPD development via stimulating mitophagy to inhibit cellular senescence and the ensuing SASP-mediated chronic inflammation.

Source: Letters in Drug Design & Discovery

DOI: 10.1016/j.lddd.2026.100331