Network Pharmacology and Experimental Research of β-Sitosterol in Treating Chronic Obstructive Pulmonary Disease via the Glucocorticoid Receptor.

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder characterized by persistent inflammation, oxidative stress, and progressive lung function decline. The therapeutic potential of β-sitosterol in COPD remains unclear. This study aimed to investigate the protective effects of β-sitosterol against COPD and elucidate its underlying mechanism. Database screening identified the glucocorticoid receptor (GR) as a potential target of β-sitosterol. A cigarette smoke-induced COPD mouse model and a cigarette smoke extract (CSE)-stimulated BEAS-2B cell model were established. Pulmonary function, lung injury-related markers, inflammation, oxidative stress, and cellular senescence were assessed using (RT-qPCR), DCFH-DA fluorescent probe assays, and senescence detection kits. The effects of β-sitosterol alone or in combination with dexamethasone (DEX) were also evaluated. β-sitosterol significantly improved pulmonary function, normalized lung injury-related markers, and attenuated inflammation, oxidative stress, and cellular senescence in both CSE-stimulated BEAS-2B cells and cigarette smoke-exposed mice. These protective effects were accompanied by increased GR expression. Moreover, β-sitosterol enhanced responsiveness to DEX, and combined treatment with β-sitosterol and DEX produced greater improvements in pulmonary function, lung injury markers, inflammation, reactive oxygen species levels, and cellular senescence than DEX treatment alone. Collectively, these findings suggest that β-sitosterol alleviates COPD-associated pathological changes, at least in part, by upregulating GR expression and enhancing the therapeutic efficacy of DEX, highlighting its potential as an adjuvant strategy for COPD treatment.