To investigate the mechanism of stigmasterol, an extract from Coicis Semen, in treating rats with a chronic obstructive pulmonary disease (COPD) model.

Forty healthy male SD rats (body weight:120±10 g) were randomly divided into four groups (n=10) using a random number table: blank control (NC) group, model (Mock) group, Stigmasterol group (stigmasterol 20 mg/kg), and stigmasterol+GW9662 group (stigmasterol 20 mg/kg+peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662 1 mg/kg). The COPD rat model was established by smoke exposure combined with intratracheal instillation of lipopolysaccharide (LPS, 1 mg/kg). After 14 d of intervention, alveolar macrophages were isolated. M1/M2 polarization was analyzed by flow cytometry; PPARγ expression was detected using qRT-PCR, Western blot, and ELISA; macrophage oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured with a Seahorse XF Analyzer; and lung tissue pathology and macrophage infiltration were observed via HE staining and immunohistochemistry.

Compared with the NC group, the Mock group exhibited a significantly increased M1/M2 ratio (P<0.01), markedly reduced PPARγ expression at both mRNA and protein levels (P<0.001), and decreased mitochondrial basal OCR, maximal OCR, and glycolytic ECAR in alveolar macrophages (P<0.01). Lung tissues showed typical histopathological damage, including alveolar destruction and inflammatory cell infiltration. Stigmasterol intervention reversed these abnormalities by decreasing the M1/M2 ratio (P<0.01), upregulating PPARγ expression (P<0.01), improving mitochondrial respiration and glycolytic capacity (as indicated by OCR and ECAR), and alleviating lung tissue histopathological damage (P<0.05). However, co-administration of the PPARγ antagonist GW9662 significantly attenuated stigmasterol’s beneficial effects on promoting M2 macrophage polarization, upregulating PPARγ expression, improving cellular metabolic reprogramming (OCR and ECAR), and protecting against lung tissue damage.

Stigmasterol from Coicis Semen ameliorates lung injury in COPD rats by activating PPARγ, which reprograms alveolar macrophage metabolism and drives M2 polarization.