Veratramine alleviates asthmatic airway remodelling via the PKM2/CREB1 lactylation/SMAD7 axis.

BACKGROUND

Veratramine is a natural steroidal alkaloid derived from plants of the genus Veratrum that exhibits anti-inflammatory potential. However, its pharmacological mechanisms and direct molecular targets in asthmatic airway remodelling remain unclear, particularly regarding its role in regulating metabolism-epigenetic crosstalk within the airway microenvironment.

OBJECTIVE

This study aimed to determine whether Veratramine downregulates pyruvate kinase M2 (PKM2) to suppress lactate accumulation, thereby inhibiting cAMP response element-binding protein 1 (CREB1) lactylation, restoring SMAD family member 7 (SMAD7) expression, and ultimately reversing transforming growth factor-β (TGF-β)-driven airway remodelling.

METHODS

A house dust mite (HDM)-induced murine asthma model was established to assess Veratramine efficacy. Molecular docking, molecular dynamics (MD) simulations, and cellular thermal shift assay (CETSA) confirmed its interaction with PKM2. Mass spectrometry, CUT&Tag sequencing, site-directed mutagenesis (K122R/Q), and adeno-associated virus (AAV)-mediated in vivo gene delivery were used to delineate the signalling axis.

RESULTS

Veratramine dose-dependently attenuated HDM-induced airway inflammation, goblet cell metaplasia, and subepithelial collagen deposition. It was shown to bind to and downregulate PKM2, thereby reducing pulmonary lactate accumulation. Mechanistically, HDM induced CREB1 lactylation at K122, limiting its conformational flexibility and promoting repression of the antifibrotic gene SMAD7, leading to TGF-β pathway activation and epithelial-mesenchymal transition (EMT). Inhibition of K122 lactylation or restoration of SMAD7 effectively reversed airway remodelling.

CONCLUSION

This study identifies a novel "PKM2-lactate-CREB1 lactylation-SMAD7" axis driving airway remodelling in asthma. Veratramine acts as a PKM2 modulator, restoring SMAD7-mediated negative feedback via metabolic reprogramming, and represents a promising lead for anti-remodelling therapy.