Pathogen-Induced Lysosomal Membrane Permeabilization: A Critical Interface Between Host Defense and Cell Death

During pathogen infection, lysosomes are not only pivotal targets exploited by pathogens to evade host defenses and induce cell death, but also an essential frontline of host protection that restricts infection by degrading invading microbes and repairing membrane damage. A broad spectrum of pathogens-including bacteria, viruses, protozoa, and fungi-can trigger lysosomal membrane permeabilization (LMP), resulting in the leakage of lysosomal contents into the cytosol. The released lysosomal factors can selectively activate distinct cell-death programs, including apoptosis, pyroptosis, ferroptosis, and necroptosis. These cell-death processes may limit pathogen dissemination by eliminating infected cells, yet they can also exacerbate disease through excessive inflammatory responses and tissue injury. In this review, we highlight recent advances and systematically discuss the determinants of lysosomal membrane stability, methods for detecting LMP, and LMP-driven cell-death modalities, and we summarize the mechanisms and consequences of pathogen-induced LMP.