Paeoniflorin Attenuates Zinc Oxide Nanoparticle-Induced Pyroptosis in HepG2 Cells via the Activation of SIRT1/TFEB Signaling Pathway

Zinc oxide nanoparticles (ZnO NPs) have been applied in biomedicine, food processing, and agricultural production. ZnO NPs can cause potential hepatotoxicity in animals and humans; however, the precise molecular mechanisms remain unclear and the effective treatment strategies are scarce. In this study, we investigated the protective effects of paeoniflorin (PF), a bioactive compound extracted from the roots of Paeoniaceae plants, on ZnO NPs-induced hepatotoxicity using a cell model. Our results showed that PF supplementation can dose-dependently attenuate ZnO NPs-induced decreases in cell viability and oxidative damage in HepG2 cells. Mechanistically, PF significantly reduced the activation of NLRP3 inflammasome, then reduced the expression of GSDMD-NT cleavage and the secretion of IL-1β and IL-18, and finally ameliorated ZnO NPs-induced pyroptosis. Furthermore, PF can directly interact with SIRT1, then deacetylate TFEB and promote autophagy-lysosome biogenesis. Overexpression of TFEB markedly attenuated ZnO NPs-induced pyroptosis. Consistently, the inhibition of SIRT1 or knockdown of TFEB both partly attenuated the protective effect of PF. Taken together, for the first time, our study demonstrated that PF can directly target SIRT1, then effectively attenuate ZnO NPs-induced pyroptosis via the activation the SIRT1/TFEB signaling pathway.