Chlamydia trachomatis regulates ferroptosis through the p53/SLC7A11 pathway to promote reproduction.

Genital tract Chlamydia trachomatis (Ct) infection is one of the most prevalent sexually transmitted infections (STIs) worldwide. However, its clinical progression is often insidious and prolonged. Understanding the mechanisms by which Ct influences cell death pathways is crucial for elucidating the pathogenic processes of this intracellular bacterium. Ferroptosis, a newly identified form of programmed cell death, is characterized by the iron-dependent accumulation of lipid peroxides. Despite its relevance, the interaction between Ct and ferroptosis remains poorly studied. In the present study, we first performed bioinformatics analysis based on RNA sequencing data under an in vitro model of Ct acute infection. Bioinformatics analysis revealed significant enrichment of differentially expressed genes in ferroptosis and p53 signaling pathways. Subsequently, we validated the hypothesis that Ct inhibits host ferroptosis by expression assays of ferroptosis-related proteins. Further cell proliferation, intracellular ferrous iron fluorescence, and lipid peroxidation assays multifaceted observations of the phenotype. Mechanistically, we found that Ct inhibition of ferroptosis acts by regulating the host p53/SLC7A11 pathway. Finally, indirect immunofluorescence assays demonstrated that ferroptosis decreases inclusion forming units (IFUs) of Ct progeny and thus affects its reproduction, which partly explains Ct's survival strategy of resisting host ferroptosis.