The ability of a host to tolerate Salmonella infection is determined by its iron status, an important element of nutritional immunity. A recent study discovered that SpvB, a potent pSLT-encoded cytotoxic agent, promotes Salmonella infection in macrophages by interfering with cellular iron metabolism. However, the underlying mechanisms of SpvB in Salmonella-related systemic iron metabolism diseases have yet to be discovered. In the study, it was discovered that SpvB promoted Salmonella to scavenge iron from the host by modulating the fundamental regulator of systemic iron metabolism i.e. the hepcidin–ferroportin axis. SpvB increased hepcidin synthesis via the STAT3 pathway, but not through the BMP/SMAD pathway. This, in turn, caused a decrease in the cellular iron exporter ferroportin, which helped to establish hypoferremia and hepatic iron accumulation. As a result of this, the restriction of iron availability was overcome, providing improved chances for Salmonella survival and propagation. Furthermore, SpvB upregulated TREM-1 signaling to enhance the production of proinflammatory molecules linked with the activation of inflammatory cells. The research lent support to a TREM-1 involvement in SpvB-related host iron metabolism malfunction and indicated that blocking TREM-1 may be an effective therapeutic approach to prevent or treat Salmonella infection.