<i>Streptococcus suis</i> Stk1 sensitizes epithelial cells to ferroptosis and exacerbates disruption of the respiratory epithelial barrier

<i>Streptococcus suis</i> serotype 2 (SS2), a significant zoonotic pathogen, initiates systemic infection by breaching the respiratory epithelial barrier. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly implicated in the pathogenesis of various infectious diseases, yet its role in SS2-induced epithelial barrier dysfunction remains unknown. Here, we demonstrate SS2 infection sensitizes airway epithelial cells to ferroptosis, leading to the accumulation of lipid peroxides, upregulation of the transcriptional repressor Snail1, and subsequent downregulation of intercellular junction proteins. This cascade compromises epithelial integrity and promotes bacterial translocation. Mechanistically, we found SS2 overwhelms the cellular redox defense system and identified bacterial eukaryotic-like serine/threonine kinase 1 (Stk1) as the key mediator of this process. Stk1 directly interacts with host protein Keap1, which stabilizes the Keap1-Nrf2 complex. This stabilization enhances the ubiquitination and subsequent proteasomal degradation of Nrf2, the master regulator of antioxidant response, thereby crippling cell's ability to neutralize lipid peroxides. In summary, this study unveils a novel virulence mechanism wherein SS2 effector Stk1 promotes Nrf2 degradation to trigger ferroptosis, ultimately leading to the disruption of respiratory epithelial barrier. These findings suggest that inhibiting ferroptosis could represent a promising therapeutic strategy for clinical prevention and treatment of SS2 infections.