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The release of progeny through the orchestrated lysis of host cells plays a crucial role for the development of new infections, though the underlying molecular mechanisms remaining largely unexplored. In this study, we identified a novel mechanism by which <jats:italic>Chlamydia<\/jats:italic> induces host cell ferroptosis to facilitate its progeny release. This process involves the degradation of the host protein SLC7A11 by the chlamydial protease-like activity factor (CPAF), resulting in glutathione depletion and subsequent cell death characterized by lipid peroxidation. Infection with a CPAF-deficient strain fails to induce host cell ferroptosis. Notably, inhibiting ferroptosis by vitamin E reduces the <jats:italic>Chlamydia<\/jats:italic> burden in low genital tract of mice and trends toward attenuation of pathology. These findings provide new insights into the conserved survival strategies of <jats:italic>Chlamydia<\/jats:italic> and understanding of its pathogenesis.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013060","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T18:16:50Z","timestamp":1744136210000},"page":"e1013060","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chlamydial protease-like activity factor targets SLC7A11 for degradation to induce ferroptosis and facilitate progeny 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