Cucurbitacin B attenuates bleomycin-induced pulmonary fibrosis by inhibiting M2 macrophage polarization via PI3K/AKT/mTOR signaling

Pulmonary fibrosis is a progressive interstitial lung disease with high mortality and few effective therapies. A key feature of this process is the persistent activation of M2 macrophages, which promote fibrosis through the release of profibrotic mediators. Cucurbitacin B (CuB), a tetracyclic triterpenoid found in Cucurbitaceae and Cruciferae plants, has been recognized for its anti-inflammatory and antitumor activities, but its role in pulmonary fibrosis has not been defined. Here, we examined the impact of CuB on bleomycin-induced pulmonary fibrosis in mice and on IL-4/IL-13-driven macrophage polarization in vitro. CuB treatment attenuated lung injury and Collagen accumulation, reduced M2 macrophage infiltration, and suppressed the profibrotic cross-talk between macrophages and fibroblasts. Mechanistic studies revealed that CuB inhibited the phosphorylation of PI3K/Akt/mTOR, a pathway critical for M2 polarization. Inhibitors of PI3K and mTOR mimicked CuB's effects, whereas an Akt Agonist partially reversed them, confirming the pathway's involvement. These findings suggest that CuB alleviates pulmonary fibrosis by restraining M2 macrophage polarization and downstream fibroblast activation through PI3K/Akt/mTOR inhibition, highlighting its potential as a candidate for antifibrotic therapy.