Chlamydia trachomatis inhibits NF-κB-dependent ferroptosis through PARP10 upregulation to promote reproduction.

UNLABELLED: Chlamydia trachomatis (Ct), an obligate intracellular pathogen, manipulates host cell death pathways to establish infection. Although ferroptosis-an iron-dependent cell death process marked by lipid peroxidation-constitutes an antimicrobial defense mechanism, its regulation during Ct infection remains in the early stages of exploration. Here, we report that Ct actively suppresses ferroptosis in host cells, with maximal inhibition at 24 hours post-infection. This suppression was demonstrated through attenuated malondialdehyde production, reduced Fe²+ accumulation, and preserved mitochondrial integrity. Transcriptomic analysis of Ct-infected cells identified PARP10 as a prominently upregulated host factor. Crucially, we discovered that Ct-induced PARP10 inhibits NF-κB activation, leading to downregulation of ferroptosis-promoting genes. Disruption of the PARP10/NF-κB axis restored ferroptosis and impaired Ct replication. Our findings unveil a non-canonical strategy wherein Ct exploits PARP10 to repress NF-κB-dependent ferroptotic defense, thereby maintaining iron/lipid peroxide homeostasis for intracellular survival. Targeting this pathway may offer novel anti-chlamydial therapeutics.

IMPORTANCE

Chlamydia trachomatis is a widespread bacterial infection and a leading cause of preventable blindness and sexually transmitted diseases. A key to its success is its ability to survive inside our cells by disarming the body's innate defense systems. We discovered that the bacteria actively block a potent form of cell death called ferroptosis by exploiting a human protein, PARP10. This previously unknown strategy allows Chlamydia to create a safe haven for its replication. Uncovering this novel bacterial survival mechanism not only deepens our understanding of the infection process but also reveals the PARP10 pathway as a promising new target for developing much-needed therapeutic drugs against this pervasive pathogen.