Formononetin ameliorates allergic asthma by inhibiting JUN and suppressing type Ⅱ immune responses mediated by ILC2 cells

OBJECTIVE: Formononetin (FM), a flavonoid with potent anti-inflammatory effect, was investigated for its therapeutic potential and underlying mechanisms in allergic asthma (AS). METHODS: An ovalbumin (OVA)-induced murine model of AS was established and treated with FM. Inflammatory responses, mucus secretion, and the activation and migration of type II innate lymphoid cells (ILC2s) were assessed using histological staining, ELISA, flow cytometry, and molecular analysis. The role of the JUN gene was further explored using the JUN agonist 15(S)-HpETE. In vitro assays were conducted to evaluate FM's effects on ILC2 proliferation and cytokine expression. RESULTS: FM significantly alleviated airway inflammation, reduced mucus hypersecretion, and lowered serum IgE levels. It decreased the abundance and activation of ILC2s in lung tissues and suppressed the expression of related cytokines and transcription factors. Notably, FM inhibited the lung-gut axis migration of ILC2s by reducing iILC2 and nILC2 levels in the small intestine and iILC2 levels in the lung. In vitro, FM suppressed ILC2 proliferation and activation. These effects were reversed by 15(S)-HpETE, suggesting a JUN-dependent mechanism. CONCLUSIONS: FM ameliorates AS by inhibiting type II immune responses and ILC2 migration via targeting JUN. These findings suggest FM as a promising candidate for asthma therapy.