Our results functionally link the increased labile cellular iron levels in FTH-deficient macrophages to rapidly expanding pathogen burdens, which contribute to uncontrolled activation of the NF-κB and inflammasome pathways, detrimental cytokine formation, and dramatically shortened survival in course of infection with the intramacrophage pathogen S. Typhimurium. Here, NFKB1 is linked to infection.