Succinate contributes to Staphylococcus aureus skin infection by reactive oxygen species-hypoxic inducible factor 1α-glycolysis axis

Skin and soft tissue infections (SSTIs) caused by Staphylococcus aureus (S. aureus), one of the most prevalent and refractory diseases in humans and animals, are potentially involved in the metabolic reprogramming of pathogens and hosts. This study identified succinate as a danger signal. Succinate elevates mitochondrial ROS (mROS) levels, leading to higher HIF1α expression and glycolysis. These changes ultimately drive inflammation. Moreover, as a metabolite shared by pathogens and hosts, succinate facilitated metabolic crosstalk during infection. Through the deletion of S. aureus sucD, our results demonstrated that succinate derived from S. aureus exacerbated infection-induced inflammation. Additionally, our observations revealed consistently high expression levels of S. aureus fumC, a downstream enzyme in succinate metabolism, during skin infection, which maintained elevated glycolysis levels through the depletion of fumarate in the infectious environment. Overall, our findings elucidated the mechanism by which succinate regulates glycolysis via the mROS-HIF1α axis and provided support for targeting bacterial metabolism as a mechanism to prevent bacterial metabolic reprogramming and the development of skin infection.