Notoginsenoside R1 attenuates idiopathic pulmonary fibrosis through neuropilin-1/type 2 innate lymphoid cells pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by excessive extracellular matrix accumulation, high mortality, and limited therapeutic options. Notoginsenoside R1 (NG-R1), a major bioactive saponin derived from Panax notoginseng, possesses notable anti-inflammatory and antioxidant properties, suggesting therapeutic potential in fibrotic diseases. This study evaluated the therapeutic efficacy and underlying mechanisms of NG-R1 in a mouse model of IPF induced by bleomycin (BLM), a chemotherapeutic agent commonly used to mimic pulmonary fibrosis. Network pharmacology analysis predicted that NG-R1 primarily targets pathways related to oxidative stress and immune regulation. In a BLM-induced mouse model of IPF, NG-R1 administration significantly alleviated pulmonary fibrosis, as indicated by improved lung histopathology, reduced hydroxyproline content and collagen deposition, and enhanced antioxidant enzyme activity. Mechanistic investigations revealed that NG-R1 downregulated neuropilin-1 (NRP1) expression in group 2 innate lymphoid cells (ILC2s), key mediators of type 2 immune responses and fibrotic progression. This modulation disrupted the TGF-β1/NRP1/IL-33/stimulation expressed gene 2 (ST2) signaling axis, resulting in decreased ILC2s infiltration and reduced secretion of profibrotic cytokines IL-13 and IL-5. Collectively, these findings demonstrate that NG-R1 mitigates pulmonary fibrosis by modulating innate immune responses via the NRP1/ILC2 axis, supporting its potential as a targeted immunopharmacological therapy for IPF.