Trimethyltin chloride (TMT) - induced vascular injury through ubiquitination proteasome pathway - regulated GPX4 degradation

Trimethyltin chloride (TMT) is a highly toxic organotin pollutant commonly found in the environment, posing serious risks to humans and animals. To explore the potential toxicity mechanism of TMT on vascular systems, we developed models exposing vascular smooth muscle cells (VSMCs) and male Balb/c mice to TMT. Levels of reactive oxygen species (ROS) and glutathione (GSH) were measured using fluorescence methods and assay kits, while the expression of genes related to glutathione peroxidase 4 (GPX4), Nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 (NRF2/HO-1) pathway, autophagy-lysosome, and ubiquitination proteasome pathway were analyzed through Western blot and immunofluorescence. The findings indicated that exposure to TMT activated the GPX4-dependent lipid peroxidation pathway, leading to cell death in VSMCs, rather than necrosis or apoptosis. This conclusion was supported by several key indicators: a dose-dependent increase in ROS levels, alongside a dose-dependent decrease in GSH and GPX4 levels. Further in-depth analysis elucidated that TMT-induced GPX4 degradation and subsequent cell death are primarily mediated by the ubiquitination-proteasome pathway. Notably, this process occurs independently of the NRF2/HO-1 signaling pathways or the autophagy-lysosome system. In conclusion, TMT exposure causes dose-dependent GPX4 degradation via the ubiquitination proteasome pathway, leading to cell death in VSMCs and vascular injury.