Formononetin as a potential therapeutic agent for asthma: evidence from in vivo and in vitro models of attenuated inflammation via cAMP/PKA pathway inhibition.

This study aims to elucidate the ameliorative effects and potential mechanisms of formononetin (FN) on airway inflammation in asthmatic rats. An ovalbumin-induced asthmatic rat model was established and treated with FN. Lung function, histopathology, apoptosis, inflammatory cytokine levels, and lipid profiles were assessed. In parallel, LPS-stimulated BEAS-2B cells were treated with FN and the cAMP/PKA pathway activator coleonol (CLE). Cell proliferation, inflammatory cytokine expression, and cAMP/PKA pathway activity were evaluated. FN significantly improved lung function, reduced airway inflammation and pathological damage, and inhibited apoptosis in asthmatic rats. It also decreased serum levels of IgE, IFN-γ, IL-4, and TNF-α, and improved lipid metabolism by lowering TC, TG, and LDL-C while increasing HDL-C. In BEAS-2B cells, FN promoted proliferation and suppressed inflammation under LPS stimulation. These effects were mediated through the inhibition of the cAMP/PKA signaling pathway, as evidenced by reduced cAMP levels and PKA phosphorylation. The protective effects of FN were partially reversed by CLE. FN ameliorates airway inflammation in asthma by modulating lipid metabolism and suppressing the cAMP/PKA signaling pathway, as demonstrated in both rat models and human bronchial epithelial cells. These findings highlight FN as a promising therapeutic candidate for asthma treatment.