STING-mediated metabolic reprogramming drives lipid peroxidation during Staphylococcus aureus infection

Metabolism serves as the foundation for all physiological activities. In recent years, it has been demonstrated that the innate immune receptor STING influences pathogen infection by modulating metabolism. Notably, fatty acid metabolism plays a crucial role in regulating cellular immune function. In this study, we found STING was activated in S. aureus-infected mammary epithelial cells, reprogramming host lipid metabolism. This activation results in lipid accumulation, increased lipid peroxide production, and GSH depletion. These effects can be mitigated by genetic ablation or pharmacological inhibition of STING. Mechanistically, STING interacts with FASN to promote de novo fatty acid synthesis, providing a substrate for the production and subsequent peroxidation of unsaturated fatty acids. The process is mediated by SCD2 and ACSL4. In summary, our study provides a new insight into the role of immune-related molecules in metabolic regulation and host defense against pathogens. These findings could inform the development of novel anti-inflammatory therapies aimed at safely inhibiting STING.