A review: Bacterial hemolysin-mediated iron dysregulation and immune cell damage synergistically drive ferroptosis

Hemolysin, a critical virulence factor of bacterial pathogens that disrupts host cell membranes, induces cytolysis and facilitates immune evasion during its infection. Ferroptosis, an iron-dependent form of regulated cell death (RCD), is characterized by the lethal accumulation of lipid peroxides and has emerged as a critical mechanism increasingly implicated in infectious pathogenesis. Iron is essential for cellular metabolism but becomes pathogenic when dysregulated; its redox activity catalyzes Fenton reactions within the iron-catalyzed Haber-Weiss cycle, generating reactive oxygen species (ROS) that propagate lipid peroxidation, a hallmark of ferroptosis. Hemolysins lyse erythrocytes, releasing hemoglobin-bound iron into iron overload. Crucially, these hemolysins also directly damage immune cells. The combined effects of iron overload and direct cytotoxicity culminate in immune cell ferroptosis, impairing host defenses and facilitating bacterial survival. This review synthesizes current knowledge on how pathogenic bacteria's hemolysin-mediated iron dysregulation and immune cell damage converge to induce ferroptosis in infection, underscoring its role in the pathogenesis. We also explore therapeutic strategies targeting hemolysins, iron chelation, and ferroptosis inhibition to mitigate disease severity and counter immune evasion.