Polystyrene nanoplastics induce pyroptosis in HepG2 cells via the YAP1-cGAS-STING signaling axis

Background: Polystyrene nanoplastics (PS-NPs) are emerging environmental contaminants with documented hepatotoxic potential, yet the mechanisms underlying their liver toxicity remain incompletely understood.

Objective: This study aimed to determine whether PS-NPs induce Pyroptosis in human hepatocellular carcinoma (HepG2) cells and to elucidate the involvement of the Yes-associated protein 1 (YAP1)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling axis.

Methods: HepG2 cells were exposed to PS-NPs, followed by evaluation of cytotoxicity, Reactive Oxygen Species (ROS) generation, and ultrastructural alterations by transmission electron microscopy (TEM). Pyroptosis-related proteins and YAP1-cGAS-STING pathway components were assessed by Western blotting, and pathway involvement was further validated using CA3 (a YAP1 inhibitor) and H151 (a STING inhibitor).

Results: PS-NPs were internalized by HepG2 cells and induced cytotoxicity accompanied by ROS accumulation, increased secretion of interleukin (IL)-1β and IL-18, and activation of pyroptosis-associated proteins, including NOD-like Receptor family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin D (GSDMD). Meanwhile, PS-NPs upregulated YAP1, cGAS, and STING. CA3 markedly attenuated PS-NPs-induced activation of the YAP1-cGAS-STING axis and Pyroptosis, whereas H151 failed to protect cells and was associated with compensatory YAP1 hyperactivation.

Conclusion: These findings indicate that PS-NPs promote hepatocyte Pyroptosis through the YAP1-cGAS-STING pathway, with YAP1 serving as a central regulator, providing mechanistic insight into PS-NPs-induced liver toxicity and identifying YAP1 as a potential therapeutic target.