Abstract

Respiratory viral infections, particularly those caused by SARS-CoV-2, induce severe pulmonary epithelial injury. Piezo1 channels, which participate in antiviral responses by regulating calcium influx to maintain intracellular calcium homeostasis, are widely expressed in respiratory epithelia. Lycium barbarum polysaccharides (LBP) are known to protect against SARS-CoV-2 by reducing viral entry and modulating immunity; however, their protective mechanisms in pulmonary epithelial cells have not been clarified. This study investigated the effect exerted by LBP on SARS-CoV-2 Spike protein (SP)-induced injury in human lung epithelial Calu-3 cells, focusing on Piezo1-mediated calcium homeostasis. LBP exhibited no cytotoxicity at concentrations ranging from 12.5 to 100 μg/mL. Notably, it could ameliorate SP-induced early apoptosis, late apoptosis, and necrosis in a concentration-dependent manner. In addition, it significantly inhibited SP-induced elevation of Caspase 3/7 activity to restore SP-impaired calcium homeostasis. The Piezo1 agonist Yoda1 aggravated SP-induced Calu-3 cell damage and calcium imbalance. LBP was observed to mitigate Yoda1-induced injury; however, it did not enhance the protective effect of the Piezo1 inhibitor GsMTx4. Further experiments have demonstrated that LBP directly binds to Piezo1 protein to mitigate the SARS-CoV-2 pseudo-virus-induced membrane tension elevation and inhibit the Yoda1-induced inward currents in Calu-3 cells. In conclusion, LBP may alleviate SP-induced Calu-3 cell damage by inhibiting Piezo1 channel, thereby intervening in SP-related pulmonary epithelial injury.