Molybdenum disulfide induces growth inhibition and autophagy-dependent hepatocyte cell death through directly binding and regulating the activity of MST2.

Two-dimensional sheet-like nanomaterial molybdenum disulfide (MoS2) has extensive potential applications in the biomedical field. Nevertheless, upon entering the body, MoS2 tends to accumulate markedly in the liver, drawing increasing attention to its potential hepatotoxicity. In this study, we demonstrated that MoS2 nanosheets exerted cytotoxic effects on the liver both in vitro and in vivo. Further exploration of the toxicity mechanism, utilizing genome-wide CRISPR-Cas9 screening and molecular biological techniques, uncovered that MST2 protein is crucial in mediating MoS2-induced cytotoxicity. Moreover, protein mass spectrometry and molecular dynamics simulation results indicated that MoS2 directly binds to MST2 protein, thereby promoting its phosphorylation and activation. Subsequently, phosphorylated MST2 protein activates the Hippo signaling pathway, which in turn suppresses liver cell proliferation. Our in vivo experiments revealed that MST2 is indispensable for MoS2-induced impairment of liver regeneration in mice and disordered liver development in zebrafish. Meanwhile, the MoS2/MST2 axis was to found induce hepatocyte death via activation of autophagy dependent on LC3 protein. Collectively, this study provides a foundation for a comprehensive understanding of the biological behavior and hepatotoxicity of MoS2, offering valuable insights for the safety assessment of nanomaterials and the rational design of future nanomedicines.