Dietary intervention with Cordyceps sinensis suppresses pulmonary fibrosis via gut–lung axis regulation and TLR4/MyD88/Nrf2 signaling

Pulmonary fibrosis (PF) is a progressive lung disease driven by inflammation and oxidative stress, with fewer effective therapeutic options. In this study, we investigated Cordyceps sinensis , a traditional edible mushroom, as a potential dietary solution. The ethanolic extract of C. sinensis (CF0), identified as the most biologically active fraction, was subsequently subjected to UPLC-Q-TOF-MS analysis. CF0 revealed a chemically diverse profile enriched in polyphenolic constituents, nucleoside analogs (including cordycepin and adenosine derivatives), sterols, sphingoid bases, and low-molecular-weight compatible solutes. We demonstrate that CF0 significantly inhibits TGF-β1-induced myofibroblast activation in vitro and preserves lung architecture in bleomycin-challenged mice in vivo. At the molecular level, the extract worked two ways: it dampened the inflammatory “fire” (the TLR4/MyD88/NF-κB pathway) and boosted the body’s natural antioxidant defense (the Nrf2/HO-1 pathway), thereby protecting lung DNA from damage. Additionally, CF0 restructured the gut microbiota ( Akkermansia, Lactobacillus ) and restored short-chain fatty acids (SCFAs). This study proposes a chemistry-biology alignment supporting a redox-centric mode of action: polyphenolic motifs and cordycepin directly engage the Keap1-Nrf2 pathway, while gut-derived SCFAs systematically inhibit NF-κB, reinforcing the gut–lung barrier. Collectively, these findings establish C. sinensis as a promising functional food that delivers multi-target anti-fibrotic protection by coordinating redox homeostasis with gut–lung axis regulation.