Methylophiopogonanone a attenuates pulmonary fibrosis by inhibiting SPP1-mediated macrophage polarization via the PI3K/Akt pathway

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal lung disease. Methylophiopogonanone A (MOA), derived from the Chinese medicinal herb Ophiopogon japonicus, has been shown to exhibit anti-inflammatory and antioxidant properties. However, the effects of MOA on pulmonary fibrosis remain unclear. This study aims to evaluate the antifibrotic effect of MOA.

Methods: The antifibrotic efficacy of MOA was evaluated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, using pirfenidone (PFD) as a positive control. Assessments included histopathology, micro-computed tomography (micro-CT), lung function tests, and serum biochemistry. In vitro, RAW 264.7 murine monocyte/macrophage cells were stimulated with BLM, lipopolysaccharide (LPS), interleukin 4 (IL-4), recombinant secreted phosphoprotein 1 (SPP1) protein, or Spp1 overexpression (OE-spp1) and treated with MOA, PFD, spp1 shRNA (sh-spp1), or the PI3K inhibitor LY294002. Transcriptomics, molecular docking, microscale thermophoresis (MST), immunohistochemistry, immunofluorescence, and Western blot were used for mechanistic exploration.

Results: MOA administration significantly attenuated BLM-induced lung fibrosis and collagen deposition, improved lung function, and did not induce hepatorenal toxicity. Integrated transcriptomic and bioinformatics analyses identified SPP1 as a key potential target. Molecular docking simulation and MST assays further confirmed a favorable binding affinity between SPP1 and MOA. MOA potently inhibited both M1 and M2 macrophage polarization in vivo and in vitro. Mechanistically, MOA attenuated BLM-induced pulmonary fibrosis by suppressing SPP1-mediated macrophage polarization via inhibition of the PI3K/Akt pathway.

Conclusions: This study identifies that MOA is a promising natural compound that alleviates pulmonary fibrosis by inhibiting SPP1-mediated macrophage polarization via the PI3K/Akt pathway.

Keywords

macrophage polarization / methylophiopogonanone A / PI3K/Akt pathway / pulmonary fibrosis / SPP1

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2026 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.