Dispersible MoS Nanosheets Activated TGF-β/Smad Pathway and Perturbed the Metabolome of Human Dermal Fibroblasts.

In postgraphene two-dimensional materials (2DMs), MoS has attracted increasing attention in the biomedical field due to its excellent physicochemical properties. However, the toxicity and biocompatibility evaluation of MoS is not fully addressed. Herein, chitosan functionalized MoS (CS-MoS) nanosheets, which showed perfect dispersibility and stability performances, were synthesized and characterized. We found that CS-MoS nanosheets inhibited the viability of human dermal fibroblasts (HDFs) moderately while causing cell membrane instability, ROS generation, and DNA damage in a dosage-dependent manner. CS-MoS nanosheets did not induce significant changes in the cell morphologies, but they seemed to impair the cell division of HDFs. CS-MoS nanosheets (100 μg/mL) activated EGFR and induced reactive oxygen species, Smad, and IL-1, which in turn led to cell inflammation and apoptosis. Furthermore, HDFs showed cellular stress responses when they were exposed to low concentrations of CS-MoS nanosheets (25 and 100 μg/mL) because most of the intracellular metabolites such as amino acids were induced at 25 μg/mL but were inhibited at 100 μg/mL. Pyroglutamic acid, phosphoric acid, and inositol might be used as biomarkers for evaluating the toxicity of CS-MoS nanosheets. Additionally, 100 μg/mL CS-MoS nanosheets inhibited glutathione metabolism and induced the imbalance of cellular redox homeostasis. It further suppressed the tricarboxylic acid cycle and other metabolic pathways, causing insufficient supply of substrates and energy for HDFs. These findings will fuel the risk assessment of MoS and other 2DMs and guide the safe material design and 2DM applications.