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Pathogenic bacteria's metabolic adaptation for survival and proliferation within hosts is a crucial aspect of bacterial pathogenesis. Here, we demonstrate that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, plays a key role as a regulator of gene expression in Staphylococcus aureus. We show that citrate activates the transcriptional regulator CcpE and thus modulates the expression of numerous genes involved in key cellular pathways such as central carbon metabolism, iron uptake and the synthesis and export of virulence factors. Citrate can also suppress the transcriptional regulatory activity of ferric uptake regulator. Moreover, we determined that accumulated intracellular citrate, partly through the activation of CcpE, decreases the pathogenic potential of S. aureus in animal infection models. Therefore, citrate plays a pivotal role in coordinating carbon metabolism, iron homeostasis, and bacterial pathogenicity at the transcriptional level in S. aureus, going beyond its established role as a TCA cycle intermediate. Author summary: Citrate is the first intermediate of the TCA cycle, and its classic role is as a participant in metabolic reactions. In this study, we explored the non-metabolic role of citrate in Staphylococcus aureus. The results suggested that citrate can influence central carbon metabolism, iron homeostasis and the expression of virulence factors by modulating the regulatory activity of the catabolite control protein E (CcpE) and ferric uptake regulator (Fur). For instance, we revealed a new axis, named citrate-CcpE-pycA, was responsible for controlling the endogenous biosynthesis of aspartate, which likely resulted in changes in metabolic adaptation in the host and influenced the pathogenesis of this important human pathogen. Thus, citrate serves as a key signaling molecule for the modulation of gene expression in S. aureus. [ABSTRACT FROM AUTHOR]