Polydatin Relieves Airway Remodeling by Inhibiting P2X7R–NLRP3‐Mediated Excessive Autophagy in Asthma

BACKGROUND: Asthma is characterized by chronic airway inflammation and remodeling. Polydatin (PD), a natural compound, has shown anti-inflammatory potential, but its role in asthma-related airway remodeling and the underlying mechanisms involving the P2X7R-NLRP3 inflammasome axis and autophagy remain unclear. METHODS: An ovalbumin-induced asthmatic mouse model and primary airway smooth muscle cells (ASMCs) were used. Mice were treated with PD or the P2X7R agonist BzATP. Assessments included airway hyperresponsiveness, histopathology, inflammatory cell counts, cytokine profiling (ELISA), flow cytometry for T-cell subsets, and protein analysis via western blot and immunofluorescence. Autophagy was evaluated by measuring LC3-I/II, Beclin-1, and acidic vesicular organelles. Key signaling molecules (P2X7R, NLRP3, ASC, caspase-1, LKB1/AMPK/mTOR) were analyzed. In vitro, ASMCs were treated with BzATP, PD, and specific inhibitors; P2X7R was silenced using siRNA. RESULTS: PD treatment significantly alleviated ovalbumin-induced airway hyperresponsiveness, inflammatory cell infiltration, goblet cell hyperplasia, and collagen deposition in mice. It restored the Th1/Th2 and Th17/Treg balance and reduced levels of airway remodeling markers (α-SMA, PCNA, VEGF, MMP-9). PD suppressed excessive autophagy (reduced LC3-I/II and Beclin-1) and modulated the LKB1/AMPK/mTOR pathway. Furthermore, PD inhibited the ATP/P2X7R axis, leading to reduced NLRP3 inflammasome activation, caspase-1 activity, and secretion of IL-1β and IL-18. In ASMCs, PD reversed BzATP-induced autophagy and NLRP3 activation. Silencing P2X7R enhanced AMPK phosphorylation, underscoring its role in the pathway. CONCLUSION: PD attenuates airway remodeling in asthma by inhibiting the ATP/P2X7R-NLRP3 inflammasome axis and subsequent excessive autophagy, partly through modulation of the LKB1/AMPK/mTOR signaling pathway. These findings highlight PD as a promising therapeutic candidate for asthma treatment.